Clinical evidence has established anti-PD-1 antibody as a transformative treatment modality for relapsed/refractory peripheral T-cell lymphoma (r/r PTCL), yet reveals a therapeutic plateau with drug resistance observed in 60% of r/r PTCL. The biological determinants underlying this resistance-particularly the complex interplay between tumor-intrinsic characteristics (including tumor mutation burden and oncogenic mutations) and immune microenvironment features (notably PD-L1 expression)-remain insufficiently illustrated. Therefore, we systematically depicted the comprehensive mutation profile of r/r PTCL patients and correlated them with the efficacy and prognosis of anti-PD-1 therapy.

Here, we enrolled a cohort of 109 patients with r/r PTCL and performed targeted next-generation sequencing of 440 cancer-associated genes. Clinical information was collected and correlated with genetic mutations. We constructed JAK3 mutant models using Jurkat and BA/F3 cell lines. We performed single-cell transcriptomics, western blotting, and flow cytometry to elucidate the molecular mechanism. Additionally, we built a JAK3-mutant syngeneic mouse model to demonstrate in vivo antitumor efficacy of Tofacitinib and anti-PD-1 therapy.

We identified and validated that PD-L1 was a predictor for the efficacy of anti-PD-1 therapy in PTCL patients. The subset of PTCL patients (13.5%) characterized by enrichment of the APOBEC-related mutation signature had worse overall survival (p=0.031) compared with non-APOBEC-enriched samples. JAK3 and EZH2 mutations were associated with lower PD-L1 expression (p<0.05), and JAK3 mutations were independently correlated with shorter progression-free survival (HR=6.07, p=0.0144). Among all types of JAK3 mutations, single-cell transcriptomics, western blotting, and flow cytometry revealed that JAK3 p.A573V and p.M511I mutations led to decreased PD-L1 expression in Jurkat and BA/F3 cell lines through inactivation of STAT3. Compared with JAK3 wild-type syngeneic mouse models, JAK3 p.A573V and p.M511I mutant mice were more sensitive to Tofacitinib but not anti-PD-1 antibody.

In conclusion, we found that JAK3 mutations, especially JAK3 p.A573V and JAK3 p.M511I mutations, lead to poor prognosis of anti-PD-1 therapy through the STAT3/PD-L1 pathway. Tofacitinib is more suitable than anti-PD-1 antibody for JAK3 mutant PTCL patients.

NCT03502629.

The p53 pathway plays an important role in role in cancer immunity. Mutation or downregulation of the proteins in the p53 pathway are prevalent in many cancers, contributing to tumor progression and immune dysregulation. Recent findings suggest that the activity of p53 within tumor cells, immune cells, and the tumor microenvironment can play an important role in modulating NK cell-mediated immunity. Consequently, efforts to restore p53 pathway activity are being actively pursued to modulate this form of immunity. This review focuses on p53 activity regulating the infiltration and activation of NK cells in the tumor immune microenvironment. Furthermore, the impact of p53 and its regulation of NK cells on immunogenic cell death within solid tumors and the abscopal effect are reviewed. Finally, future avenues for therapeutically restoring p53 activity to improve NK cell-mediated antitumor immunity and optimize the effectiveness of cancer therapies are discussed.

MicroRNAs (miRNAs) are a class of small non-coding RNAs which are associated with post-transcriptional regulation of gene expression. Dysfunction or aberrant expression of miRNAs is predominant in various malignancies including lung cancer. Lung cancer is one of the commonest causes of cancer-related death worldwide, with a five-year survival of only 10-20%. The present review summarizes the current understanding of the role of miRNAs in the development and progression of human lung cancer and their therapeutic potential. Also, we briefly discuss the canonical biogenetic pathway of miRNAs followed by a detailed illustration on how miRNAs regulate human lung cancer progression in various ways. Furthermore, we focus on how miRNAs contribute to the crosstalk between cancer cells and different cells in the tumor microenvironment in the context of lung cancer. Finally, we illustrate how different miRNAs are used as a prognostic and diagnostic biomarker for lung cancer and the ongoing miRNA-associated clinical trials. In conclusion, we discuss how targeting miRNAs can be a potential therapeutic means in the treatment of human lung cancer.

Prostate cancer remains a leading cause of cancer-related mortality in men, with advanced stages posing significant treatment challenges due to high morbidity and mortality. Among genetic alterations, TP53 mutations are among the most prevalent in cancers and are strongly associated with poor clinical outcomes and therapeutic resistance. This review investigates the role of TP53 mutations in prostate cancer progression, prognosis, and therapeutic development. A comprehensive analysis of preclinical and clinical studies was conducted to elucidate the molecular mechanisms, clinical implications, and potential therapeutic approaches associated with TP53 alterations in prostate cancer. TP53 mutations are highly prevalent in advanced stages, contributing to genomic instability, aggressive tumor phenotypes, and resistance to standard treatments. Emerging evidence supports the utility of liquid biopsy techniques, such as circulating tumor DNA analysis, for detecting TP53 mutations, providing prognostic value and facilitating early intervention strategies. Novel therapeutic approaches targeting TP53 have shown promise in preclinical settings, but their clinical efficacy requires further validation. Overall, TP53 mutations represent a critical biomarker for disease progression and therapeutic response in prostate cancer. Advances in detection methods and targeted therapies hold significant potential to improve outcomes for patients with TP53-mutated prostate cancer. Further research is essential to integrate TP53-based strategies into routine clinical practice.

This review examines various classes of drugs, focusing on their therapeutic and adverse effects, particularly in relation to immunostimulation. We emphasize the potential of new approach methodologies (NAMs) to study both expected and unexpected immunostimulatory effects. By evaluating the modes of action of different immunostimulatory drugs, we aim to provide insights into effectively assessing unwanted immunostimulatory responses. The review begins by exploring drugs that stimulate the immune system-including immunostimulants, monoclonal antibodies, chemotherapeutics, and nucleic acid-based drugs-to outline NAMs that could be employed to evaluate immunostimulation.

The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.

Recent advancements in microRNAs (miRNAs) research have revealed their key roles in both normal physiological processes and pathological conditions, leading to potential applications in diagnostics and therapeutics. However, the path forward is fraught with several scientific and technical challenges. This review article briefly explores the milestones of the discovery, biogenesis, functions, and application for clinical diagnostic and therapeutic strategies of miRNAs. The potential challenges and future directions are also discussed to fully harness their capabilities.

We have previously shown that general deletion of the gene encoding the p53-inducible Mir34a microRNA enhances the number and invasion of colitis-associated colorectal cancers (CACs) in mice. Since the p53-pathway has been implicated in tumor-suppression mediated by cells in the tumor microenvironment (TME) we deleted Mir34a in myeloid cells and characterized CACs in these with scRNA-Seq (single cell RNA sequencing). This revealed an increase in specific macrophage subtypes, such as Cdk8+ macrophages and Mrc1+, M2-like macrophages. The latter displayed elevated expression of 21 known Mir34a target mRNAs, including Csf1r, Axl, Foxp1, Ccr1, Nampt, and Tgfbr2, and 32 predicted Mir34a target mRNAs. Furthermore, Mir34a-deficient BMDMs showed enhanced migration, elevated expression of Csf1r and a shift towards M2-like polarization when compared to Mir34a-proficient BMDMs. Concomitant deletion of Csf1r or treatment with a Csf1r inhibitor reduced the CAC burden and invasion in these mice. Notably, loss of myeloid Mir34a function resulted in a prominent, inflammatory CAC cell subtype, which displayed epithelial and macrophage markers. These cells displayed high levels of the EMT transcription factor Zeb2 and may therefore enhance the invasiveness of CACs. Taken together, our results provide in vivo evidence for a tumor suppressive role of myeloid Mir34a in CACs which is, at least in part, mediated by maintaining macrophages in an M1-like state via repression of Mir34a targets, such as Csf1r. Collectively, these findings may serve to identify new therapeutic targets and approaches for treatment of CAC.

The tumour suppressor gene p53 is one of the most frequently mutated genes in lung cancer and these defects are associated with poor prognosis, albeit some debate exists in the lung cancer field. Despite extensive research, the exact mechanisms by which mutant p53 proteins promote the development and sustained expansion of cancer remain unclear. This review will discuss the cellular responses controlled by p53 that contribute to tumour suppression, p53 mutant lung cancer mouse models and characterisation of p53 mutant lung cancer. Furthermore, we discuss potential approaches of targeting mutant p53 for the treatment of lung cancer.

The PD1/PD-L1 axis plays an important immunosuppressive role during the T-cell-mediated immune response, which is essential for the physiological homeostasis of the immune system. The biology of the immunological microenvironment is extremely complex and crucial for the development of treatment strategies for immunotherapy. Characterization of the immunological, genomic or transcriptomic landscape of cancer patients could allow discrimination between responders and non-responders to anti-PD-1/PD-L1 therapy. Immune checkpoint inhibitor (ICI) therapy has shown remarkable efficacy in a variety of malignancies in landmark trials and has fundamentally changed cancer therapy. Current research focuses on strategies to maximize patient selection for therapy, clarify mechanisms of resistance, improve existing biomarkers, including PD-L1 expression and tumor mutational burden (TMB), and discover new biomarkers. In this review, we focus on the function of the PD-1/PD-L1 signaling pathway and discuss the immunological, genomic, epigenetic and transcriptomic landscape in cancer patients receiving anti-PD-1/PD-L1 therapy. Finally, we provide an overview of the clinical trials testing the efficacy of antibodies against PD-1/PD-L1.

Colorectal cancer, characterized by its high incidence, concealed early symptoms, and poor prognosis at advanced stages, ranks as the third leading cause of cancer-related deaths worldwide. Astragalus membranaceus (AM) refers to the dried roots of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao and Astragalus membranaceus (Fisch.) Bge. In the theory of Traditional Chinese Medicine (TCM), it is believed to have the functions of tonifying qi and lifting yang, as well as generating body fluids and nourishing blood. It can effectively treat cancer caused by the deficiency of vital energy and susceptibility to external diseases. Modern research has confirmed that the active components of AM, including Astragalus polysaccharides, flavonoids (formononetin and calycosin), Astragalus saponins (Astragaloside I and Astragaloside III), and Astragalus nanovesicles, are effective in the treatment of colorectal cancer. The mechanisms mainly involve inducing apoptosis, inhibiting tumor angiogenesis and the metastasis of cancer cells, regulating the cell cycle and tumor microenvironment, and reversing drug resistance. Moreover, it offers a synergistic enhancement when used in combination with chemotherapy, radiotherapy, targeted therapy, or surgical treatment. AM also has great potential in treating colorectal cancer when combined with other herbs. This review summarizes the relevant research findings on the treatment of colorectal cancer with AM, as well as its main pharmacological effects and molecular mechanisms, aiming to provide guidance for the development of new drugs, and offer direction for the conduct of more related research and promoting the development and application of AM.

The spatial role of M1 and M2 tumor-associated macrophages (M1/M2 TAMs) in precision medicine remains unclear. EGFR and TP53 are among the most frequently mutated genes in lung adenocarcinoma. We characterized the mutation status and density of M1/M2 TAMs within tumor islets and stroma in 117 lung adenocarcinomas using next-generation sequencing and immunohistochemistry, respectively. Stromal M1 TAMs were positively correlated with disease progression and smoking history. In contrast, islet M1/M2 TAMs were predominantly found in tumors with wild-type TP53 (wtp53) but not associated with EGFR status. The presence of wtp53 was associated with the spatial distribution of M1/M2 TAMs in tumor islets and stroma. Additionally, dominance of islet M1 TAMs and M1-signature were significantly associated with improved survival in patients with wtp53 lung adenocarcinoma, unlike in those with mutant TP53. Conditioned medium from M1 macrophages (M1 CM) induced apoptosis in wtp53 cells through increased p53 accumulation. We found that interferons in M1 CM activate JAK1/TYK2 via IFNARs, leading to enhanced STAT1 expression and Y701 phosphorylation. This activation facilitates p53-STAT1 interactions, reduces the interaction between p53 and MDM2, and subsequently decreases p53 ubiquitination. M1 CM inhibited tumorigenesis, and silencing p53 reduced the anti-tumor efficacy of polyinosinic:polycytidylic acid (poly I:C) in vivo. Furthermore, higher M1-signature was significantly associated with better responses and survival following anti-PD1 treatment in wtp53 melanomas. IFNs/STAT1/p53 signaling was critical for the anti-tumor activity of M1 macrophages. These findings suggest that p53 modulates the spatial balance of M1/M2 TAMs, and the tumoricidal effects of M1 TAMs depend on p53 status. Thus, p53 companion diagnostics could facilitate the development of M1-oriented therapies, which may be particularly beneficial for wtp53 patients when combined with immunotherapy.

Exosomal non-coding RNAs (ncRNAs) have become essential contributors to advancing and treating lung cancers (LCs). The development of liquid biopsies that utilize exosomal ncRNAs (exo-ncRNAs) offers an encouraging method for diagnosing, predicting, and treating LC. This thorough overview examines the dual function of exo-ncRNAs as both indicators for early diagnosis and avenues for LC treatment. Exosomes are tiny vesicles secreted by various cells, including cancerous cells, enabling connection between cells by delivering ncRNAs. These ncRNAs, which encompass circular RNAs, long ncRNAs, and microRNAs, participate in the modulation of gene expression and cellular functions. In LC, certain exo-ncRNAs are linked to tumour advancement, spread, and treatment resistance, positioning them as promising non-invasive indicators in liquid biopsies. Additionally, targeting these ncRNAs offers potential for innovative treatment approaches, whether by suppressing harmful ncRNAs or reinstating the activity of tumour-suppressing ones. This review emphasizes recent developments in the extraction and analysis of exo-ncRNAs, their practical applications in LC treatment, and the challenges and prospects for translating these discoveries into clinical usage. Through this detailed examination of the current state of the art, we aim to highlight the significant potential of exo-ncRNAs for LC diagnostics and treatments.

Small extracellular vesicles (sEVs), carrying PD-L1, have been implicated in immune evasion and tumor progression. However, understanding how PD-L1 sEVs are secreted still needs to be improved. We found that the secretion dynamics of PD-L1 sEVs is similar to that of other sEVs. Intracellular calcium and the associated downstream PKC signaling plays pivotal roles in releasing PD-L1 sEVs in non-small cell lung cancer cells (NSCLC). Particularly, we observed that knocking down PKCα has profound impacts on PD-L1 sEVs secretion, especially in the resting state and in the activated state, when induced by an intracellular calcium rise. Furthermore, our study revealed that PKCα regulates PD-L1 expression and PD-L1 sEVs secretion by influencing STAT1 phosphorylation and nuclear translocation in a p53-dependent manner. Notably, p53 can regulate STAT1 phosphorylation and nuclear localization, but it does not affect PKCα expression. This suggests that PKCα plays a significant role in regulating PD-L1 expression. Our findings suggest that targeting PKCα to modulate PD-L1 dynamics in NSCLC may be a promising therapeutic strategy to enhance the efficacy of immunotherapeutic interventions.

Glioblastoma is one of the most aggressive human brain tumors. The prognosis is unfavorable and treatment effects are relatively low. However, temozolomide (TMZ) chemotherapy may prolong patients' survival.

The anti-glioma effect of clofazimine used in immunotherapy is examined in vivo.

Method of obtaining TMZ-resistant GB cells included treatment of T98G glioblastoma cells with 150 μmol/l TMZ. To confirm resistance to TMZ, MTT assay was performed according to the manufacturer's protocol. Untreated cells were used as a control group. C6 glioma cells were stereotactically implanted into the brain of Wistar rats and irradiated (24 Gy) in combination with oral administration of TMZ (20 mg/ kg) and clofazimine (CFZ) (30 mg/kg). This was followed by subsequent immunotherapy including tumor cell and dendritic cell vaccines. Neurovisualisation, immunocytochemical and immunohistochemical assays were used and animals' survival was analyzed with Kaplan-Meier estimator.

T98G resistant glioblastoma cell line is characterized by immunoreactive β-catenin, CD133, CD44, and N-cadherin as compared to the control cell line. The IC 50 of clofazimine for T98G glioblastoma cell line is 38.3 ± 4,1 μmol/l, for C6 rat glioma cell line is 37,6 ± 3,2 μmol/l. Clofazimine enhanced the cytotoxic activity of temozolomide, paclitaxel, and carboplatin in cancer cells of T98G line as compared to the control group. The cytotoxic effect of lomustine and carboplatin against T98G resistant glioblastoma cells was also enhanced by Clofazimine. Tumor cell vaccine (TCV) and dendritic cell vaccine (DCV) in combination with clofazimine produces a stronger anti-tumor immune response in C6 glioma. This is evident with development of local inflammatory reaction with higher content of interleukin 1β and 18 in serum, as well as greater level of IBA1+, CD68 + in pro-inflammatory microglia of neoplastic tissues. Combined use of DCV and clofazimine results in higher survival rates in experimental animals (- 90 ± 7 days against 45 ± 5 days) in the treated group with chemoradiation therapy (CRT).

Combination of clofazimine and immunotherapy enhances anti-glioma effect of TMZ in an in vivo model experiment.

Immunosuppressive tumor microenvironment (ITM) severely limited the efficacy of immunotherapy against triple-negative breast cancer (TNBC). Herein, Apt-LPR, a light-activatable photodynamic therapy (PDT)/RNAi immune synergy-enhancer was constructed by co-loading miR-34a and photosensitizers in cationic liposomes (in phase III clinical trial). Interestingly, the introduction of tumor-specific aptamers creates a special "Liposome-Aptamer-Target" interface, where the aptamers are initially in a "lying down" state but transform to "standing up" after target binding. The interfacing mechanism was elaborately revealed by computational and practical experiments. This unique interface endowed Apt-LPR with neutralized surface potential of cationic liposomes to reduce non-specific cytotoxicity, enhanced DNase resistance to protect aptamers, and preserved target-binding ability for selective drug delivery. Upon near-infrared irradiation, the generated reactive oxygen species would oxidize unsaturated phospholipids to destabilize both liposomes and lysosomes, realizing stepwise lysosomal escape of miR-34a for tumor cell apoptosis and downregulation of PD-L1 to suppress immune escape. Together, tumor-associated antigens released from PDT-damaged mitochondria and endoplasmic reticulum could activate the suppressive immune cells to establish an "immune hot" milieu. The collaborative immune-enhancing strategy effectively aroused systemic antitumor immunity and inhibited primary and distal tumor progression as well as lung metastasis in 4T1 xenografted mouse models. The photo-controlled drug release and specific tumor-targeting capabilities of Apt-LPR were also visualized in MDA-MB-231 xenografted zebrafish models. Therefore, this photoswitchable PDT/RNAi immune stimulator offered a powerful approach to reprogramming ITM and reinforcing cancer immunotherapy efficacy.

Lung cancer is a significant cause of cancer-related death worldwide. It can be broadly categorised into small-cell lung cancer (SCLC) and Non-small cell lung cancer (NSCLC). Surgical intervention, radiation therapy, and the administration of chemotherapeutic medications are among the current treatment modalities. However, the application of chemotherapy may be limited in more advanced stages of metastasis due to the potential for adverse effects and a lack of cell selectivity. Although small-molecule anticancer treatments have demonstrated effectiveness, they still face several challenges. The challenges at hand in this context comprise insufficient solubility in water, limited bioavailability at specific sites, adverse effects, and the requirement for epidermal growth factor receptor inhibitors that are genetically tailored. Bio-macromolecular drugs, including small interfering RNA (siRNA) and messenger RNA (mRNA), are susceptible to degradation when exposed to the bodily fluids of humans, which can reduce stability and concentration. In this context, nanoscale delivery technologies are utilised. These agents offer encouraging prospects for the preservation and regulation of pharmaceutical substances, in addition to improving the solubility and stability of medications. Nanocarrier-based systems possess the notable advantage of facilitating accurate and sustained drug release, as opposed to traditional systemic methodologies. The primary focus of scientific investigation has been to augment the therapeutic efficacy of nanoparticles composed of lipids. Numerous nanoscale drug delivery techniques have been implemented to treat various respiratory ailments, such as lung cancer. These technologies have exhibited the potential to mitigate the limitations associated with conventional therapy. As an illustration, applying nanocarriers may enhance the solubility of small-molecule anticancer drugs and prevent the degradation of bio-macromolecular drugs. Furthermore, these devices can administer medications in a controlled and extended fashion, thereby augmenting the therapeutic intervention's effectiveness and reducing adverse reactions. However, despite these promising results, challenges remain that must be addressed. Multiple factors necessitate consideration when contemplating the application of nanoparticles in medical interventions. To begin with, the advancement of more efficient delivery methods is imperative. In addition, a comprehensive investigation into the potential toxicity of nanoparticles is required. Finally, additional research is needed to comprehend these treatments' enduring ramifications. Despite these challenges, the field of nanomedicine demonstrates considerable promise in enhancing the therapy of lung cancer and other respiratory diseases.

Tumor cells can escape immune surveillance by changing their own escape or expressing abnormal genes and proteins, resulting in unlimited proliferation and invasive growth of cells. These changes are related to microRNAs (miRNAs), which reduce the killing effect of immune cells, devastate the immune response, and interfere with apoptosis through the aberrant expression of relevant miRNAs. In the preliminary phase of this study, miRNAs in clinical plasma exosomes of colorectal cancer patients were differentially analyzed by RNA sequencing technology, and miR-372-5p derived from extracellular vesicles (sEVs) was found to be a key signaling molecule mediating the regulation of macrophages by colorectal cancer (CRC). miRNA-372-5p is upregulated in colorectal cancer patient tissues and serum, as well as colorectal cancer cell lines and their exosomes. Subsequently, we found that macrophages could take up sEV secreted by colorectal cancer cells HCT116, affecting the expression of the immune checkpoint PD-L1, resulting in the generation of a tumor-immunosuppressive microenvironment and suppression of T cell activation in CRC. Gene enrichment mapping and database revealed that miR-372-5p regulates PD-L1 expression in colorectal cancer through the homologous phosphatase-tensin (PTEN)-phosphatidylinositol 3-kinase-protein kinase B (AKT)-nuclear factor-κB (NF-κB) pathway. Further studies confirmed that miRNA-372-5p-treated macrophages co-cultured with T cells affected the regulation of PD-L1 expression through the PTEN/AKT/NF-κB signaling pathway, resulting in decreased CD3+CD8+ T cell activity, decreased cytokine IL-2 and increased IFN-γ. And miRNA-372-5p could down-regulate the expression of PD-L1 in HCT116 through the PTEN/AKT/NF-κB pathway, inhibit tumor cell proliferation and promote apoptosis. Conclusion: Colorectal cancer cell-derived exosome miR-372-5p can be phagocytosed by colorectal cancer and macrophage cells, regulate the expression of PD-L1 in colorectal cancer cells and macrophages by targeting the PTEN/AKT/NF-κB pathway, and induce the immunosuppressive microenvironment of CRC to promote CRC development. This suggests that inhibiting the secretion of HCT116-specific sEV-miR-372-5p or targeting PD-L1 in tumor-associated macrophages could be a novel approach for CRC treatment and possibly a sensitizing approach for CRC anti-PD-L1 therapy.

The treatment of cancers with immunotherapies has yielded significant milestones in recent years. Amongst these immunotherapeutic strategies, the FDA has approved several checkpoint inhibitors (CPIs), primarily Anti-Programmed Death-1 (PD-1) and Programmed Death Ligand-1/2 (PDL-1/2) monoclonal antibodies, in the treatment of various cancers unresponsive to immune therapeutics. Such treatments resulted in significant clinical responses and the prolongation of survival in a subset of patients. However, not all patients responded to CPIs, due to various mechanisms of immune resistance. One such mechanism is that, in addition to PD-1 expression on CD8 T cells, other inhibitory receptors exist, such as Lymphocyte Activation Gene 3 (LAG-3), T cell Immunoglobulin Mucin 3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors might be active in the presence of the above approved CPIs. Clearly, it is clinically challenging to block all such inhibitory receptors simultaneously using conventional antibodies. To circumvent this difficulty, we sought to target a potential transcription factor that may be involved in the molecular regulation of more than one inhibitory receptor. The transcription factor Yin Yang1 (YY1) was found to regulate the expression of PD-1, LAG-3, and TIM3. Therefore, we hypothesized that targeting YY1 in CD8 T cells should inhibit the expression of these receptors and, thus, prevent the inactivation of the anti-tumor CD8 T cells by these receptors, by corresponding ligands to tumor cells. This strategy should result in the prevention of immune evasion, leading to the inhibition of tumor growth. In addition, this strategy will be particularly effective in a subset of cancer patients who were unresponsive to approved CPIs. In this review, we discuss the regulation of LAG-3 by YY1 as proof of principle for the potential use of targeting YY1 as an alternative therapeutic approach to preventing the immune evasion of cancer. We present findings on the molecular regulations of both YY1 and LAG-3 expressions, the direct regulation of LAG-3 by YY1, the various approaches to targeting YY1 to evade immune evasion, and their clinical challenges. We also present bioinformatic analyses demonstrating the overexpression of LAG-3, YY1, and PD-L1 in various cancers, their associations with immune infiltrates, and the fact that when LAG-3 is hypermethylated in its promoter region it correlates with a better overall survival. Hence, targeting YY1 in CD8 T cells will result in restoring the anti-tumor immune response and tumor regression. Notably, in addition to the beneficial effects of targeting YY1 in CD8 T cells to inhibit the expression of inhibitory receptors, we also suggest targeting YY1 overexpressed in the tumor cells, which will also inhibit PD-L1 expression and other YY1-associated pro-tumorigenic activities.

An accurate assessment of p53's functional statuses is critical for cancer genomic medicine. However, there is a significant challenge in identifying tumors with non-mutational p53 inactivation which is not detectable through DNA sequencing. These undetected cases are often misclassified as p53-normal, leading to inaccurate prognosis and downstream association analyses. To address this issue, we built the support vector machine (SVM) models to systematically reassess p53's functional statuses in TP53 wild-type (TP53WT) tumors from multiple The Cancer Genome Atlas (TCGA) cohorts. Cross-validation demonstrated the good performance of the SVM models with a mean area under the receiver operating characteristic curve (AUROC) of 0.9822, precision of 0.9747, and recall of 0.9784. Our study revealed that a significant proportion (87%-99%) of TP53WT tumors actually had compromised p53 function. Additional analyses uncovered that these genetically intact but functionally impaired (termed as predictively reduced function of p53 or TP53WT-pRF) tumors exhibited genomic and pathophysiologic features akin to TP53-mutant tumors: heightened genomic instability and elevated levels of hypoxia. Clinically, patients with TP53WT-pRF tumors experienced significantly shortened overall survival or progression-free survival compared to those with predictively normal function of p53 (TP53WT-pN) tumors, and these patients also displayed increased sensitivity to platinum-based chemotherapy and radiation therapy.

Tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT) play crucial roles in the initiation and progression of tumors. TME is composed of various cell types, such as immune cells, fibroblasts, and endothelial cells, as well as non-cellular components like extracellular matrix (ECM) proteins and soluble factors. These elements interact with tumor cells through a complex network of signaling pathways involving cytokines, growth factors, metabolites, and non-coding RNA-carrying exosomes. Hypoxic conditions within the TME further modulate these interactions, collectively influencing tumor growth, metastatic potential, and response to therapy. EMT represents a dynamic and reversible process where epithelial cells undergo phenotypic changes to adopt mesenchymal characteristics in several cancers, including breast cancers. This transformation enhances cell motility and imparts stem cell-like properties, which are closely associated with increased metastatic capability and resistance to conventional cancer treatments. Thus, understanding the crosstalk between the TME and EMT is essential for unraveling the underlying mechanisms of breast cancer metastasis and therapeutic resistance. This review uniquely examines the intricate interplay between the tumor TME and epithelial-mesenchymal transition EMT in driving breast cancer metastasis and treatment resistance. It explores the therapeutic potential of targeting the TME-EMT axis, specifically through CD73-TGF-β dual-blockade, to improve outcomes in triple-negative breast cancer. Additionally, it underscores new strategies to enhance immune checkpoint blockade (ICB) responses by modulating EMT, thereby offering innovative insights for more effective cancer treatment.

Liver cancer is the third leading cause of cancer-related mortality worldwide. HCC, the most common type of primary liver cancer, is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally occurring small noncoding RNAs, play crucial roles in HCC by simultaneously modulating the expression of multiple genes in a fine-tuning manner. Significant progress has been made in understanding how miRNAs influence key oncogenic pathways, including cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), as well as their role in modulating the immune microenvironment in HCC. Due to the unexpected stability of miRNAs in the blood and fixed HCC tumors, recent advancements also highlight their potential as noninvasive diagnostic tools. Restoring or inhibiting specific miRNAs has offered promising strategies for targeted HCC treatment by suppressing malignant hepatocyte growth and enhancing antitumor immunity. In this comprehensive review, we consolidate previous research and provide the latest insights into how miRNAs regulate HCC and their therapeutic and diagnostic potential. We delve into the dysregulation of miRNA biogenesis in HCC, the roles of miRNAs in the proliferation and apoptosis of malignant hepatocytes, angiogenesis and metastasis of HCC, the immune microenvironment in HCC, and drug resistance. We also discuss the therapeutic and diagnostic potential of miRNAs and delivery approaches of miRNA drugs to overcome the limitations of current HCC treatment options. By thoroughly summarizing the roles of miRNAs in HCC, our goal is to advance the development of effective therapeutic drugs with minimal adverse effects and to establish precise tools for early diagnosis of HCC.

The p53 gene is one of the genes most closely associated with human tumors and has become a popular target for tumor drug design. Currently, p53-based gene therapy techniques have been developed, but these therapies face challenges such as immaturity, high safety hazards, limited efficacy, and low patient acceptance. However, researchers are no less enthusiastic about the treatment because of its theoretical potential to treat cancer. In this paper, the advances in p53-based gene therapy and related nucleic acid delivery technologies were reviewed and prospected in order to support further development in this field.

Murine double minute 2 (MDM2) plays an essential role in the cell cycle, apoptosis, DNA repair, and oncogene activation through p53-dependent and p53-independent signaling pathways. Several preclinical studies have shown that MDM2 is involved in tumor immune evasion. Therefore, MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention. In recent years, immune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic. However, the effectiveness of a single agent is only approximately 20%-40%, which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins. Here, we reviewed the role of MDM2 in regulating the immune microenvironment, tumor immune evasion, and hyperprogression during immunotherapy. In addition, we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tumors with MDM2 overexpression or amplification. The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.

MicroRNAs (MIRs) play a crucial role in colorectal cancer (CRC) development and metastasis by regulating immune responses. Tumour-infiltrating lymphocytes (TILs) are an important predictive factor in many cancers, but, their association with microRNAs have not been studied well in colorectal cancer. Three microRNAs (MIR34A, MIR31 & MIR21), the roles of which in tumorigenesis is well-studied and which also possess immunomodulatory effect, were identified by extensive literature search. Of these, MIR34A acts as a tumour suppressor, MIR21 is considered an onco-MIR, and MIR31 displays both tumour-suppressing and oncogenic properties, making it ambiguous. This study examines the relationship between these three micro-RNAs and TILs in CRC.

Conducted over 18 months at a tertiary cancer care hospital in southern India, this unicentric observational study included 69 cases. These cases were analyzed for miR expression using q-RT-PCR, TILs density through hematoxylin & eosin(H&E) slide examination, and p53 and beta-catenin expression via immunohistochemistry (IHC). Correlations between non-parametric variables were assessed using Chi-square and Spearman correlation tests.

The study found significantly higher MIR34A expression in patients aged 60 years and less (26/41, p=0.024) and a higher prevalence of MIR21 in male patients (23/35, p=0.012). TILs at the tumour advancing front were categorized as low (≤10 %) or high (≥15 %). Among the 36 cases with low TILs, high MIR34A and high MIR31 expressions were observed in 24 cases (p=0.016) and 23 cases (p=0.03), respectively. Conversely, 21 of 33 cases with high TILs had low expressions of both MIR34A and MIR31. High TILs were more common in early-stage CRC (TNM stages I-IIIA), with 20 out of 28 cases, compared to 28 of 41 cases in later stages (IIIB-IVC) exhibiting low TILs (p=0.003). Aberrant p53 expression correlated with lower MIR34A levels, consistent with TCGA data.

Lower MIR34A and MIR31 levels are associated with higher TILs density in CRC. Unlike other cancers where MIR34A has anti-tumour effects, there was no statistically significant correlation between its expression and the pT or TNM stages in this study. Increased TILs being a good prognostic indicator, this suggests MIR34A and MIR31 may help CRC cells evade immune surveillance. Aberrant p53 expression downregulates MIR34A, underscoring the therapeutic potential of miRs.

The protein p53, encoded by the most frequently mutated gene TP53 in human cancers, has diverse functions in tumor suppression. As a best known transcription factor, p53 can regulate various fundamental cellular responses, ranging from the cell-cycle arrest, DNA repair, senescence to the programmed cell death (PCD), which includes autophagy, apoptosis, ferroptosis, cuproptosis, pyroptosis and disulfidoptosis. Accumulating evidence has indicated that the tumor microenvironment (TME), N6-methyladenosine (m6A) modification and diverse PCD are important for the progression, proliferation and metastases of cancers.

This paper aims to systematically and comprehensively summarize the multiple roles of p53 in the development of cancers from the regulation of TME, m6A Modification and diverse PCD.

TME, a crucial local homeostasis environment, influences every step of tumorigenesis and metastasis. m6A, the most prevalent and abundant endogenous modification in eukaryotic RNAs, plays an essential role in various biological processes, containing the progression of cancers. Additionally, PCD is an evolutionarily conserved mechanism of cell suicide and a common process in living organisms. Some forms of PCD contribute to the occurrence and development of cancer. However, the complex roles of p53 within the TME, m6A modification and diverse PCD mechanisms are still not completely understood. Presently, the function roles of p53 including the wild-type and mutant p53 in different context are summarized. Additionally, the interaction between the cancer immunity, cancer cell death and RNA m6A methylation and the p53 regulation during the development and progress of cancers were discussed. Moreover, the key molecular mechanisms by which p53 participates in the regulation of TME, m6A and diverse PCD are also explored. All the findings will facilitate the development of novel therapeutic approaches.

The most widely used cancer therapy is radiation therapy, but radiation damage to healthy tissues, particularly the gastrointestinal (GI) system, frequently reduces its effectiveness. This study investigates whether etoricoxib-loaded nanostructured lipid carriers (Et-NLC) could help shield the rat jejunum from radiation damage. Gamma irradiation (6 Gy) was used to damage the jejunum of Wistar albino rats, and then Et or Et-NLC (10 mg/kg b.w.) was administered orally for 14 days. It was found that the amounts of glutathione S-transferase (GST), superoxide dismutase (SOD), and nitric oxide (NO) decreased after irradiation but increased after Et-NLC therapy. Molecular analysis showed radiation-induced expression of microRNA-34a (miR34a), which may be involved in cellular stress response. Et-NLC treatments modulated the expression of miR34a, suggesting possible regulatory roles. Western blot analysis revealed changes in P53, interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and cyclooxygenase-2 (COX-2) levels. Et-NLC treatments decreased TNF-α, IL-6, IL-10, and COX-2 levels, indicating anti-inflammatory actions. DNA fragmentation analysis revealed a decrease in apoptotic activity after Et-NLC treatments. A histopathological examination confirmed that Et-NLC treatments had attenuated radiation damage, which had improved vascularization and reduced inflammation. The findings show that Et-NLC is more effective than Et-alone at reducing damage to the jejunum caused by radiation by controlling inflammation, oxidative stress, and apoptotic activity.

Several microRNAs (miRNAs), including miR-221-5p, Let-7b-5p, miR-21-5p, miR-9-5p, miR-126-3p, and miR-222-3p, were recently found to be enriched in circulating exosomes of patients with non-small cell lung cancers (NSCLCs). These miRNAs distinguished cancer cases from controls with high precision and were predicted to modulate the expression of genes within the oncogenic LINE-1 regulatory network. To test this hypothesis, plasma exosomes from controls, early, and late-stage NSCLC patients were co-cultured with non-tumorigenic lung epithelial cells for 72 h and processed for measurements of gene expression. Exosomes from late-stage NSCLC patients markedly increased the mRNA levels of LINE-1 ORF1 and ORF2, as well as the levels of target miRNAs in naïve recipient cells compared to saline or control exosomes. Late-stage exosomes also modulated the expression of oncogenic targets within the LINE-1 regulatory network, namely, ICAM1, AGL, RGS3, RGS13, VCAM1, and TGFβ1. In sharp contrast, exosomes from controls or early-stage NSCLC patients inhibited LINE-1 expression, along with many of the genetic targets within the LINE-1 regulatory network. Thus, late-stage NSCLC exosomes activate LINE-1 and miRNA-regulated oncogenic signaling in non-tumorigenic, recipient lung bronchial epithelial cells. These findings raise important questions regarding lung cancer progression and metastasis and open the door for the exploration of new therapeutic interventions.

The combination of nanoparticles and tumor-targeting bacteria for cancer immunotherapy can overcome the shortcomings of poor nanoparticle accumulation, limited penetration, and restricted distribution. However, it remains a great challenge for the hybrid system to improve therapeutic efficacy through the simultaneous and controllable regulation of immune cells and tumor cells. Herein, a hybrid therapeutic platform is rationally designed to achieve immune cascade-augmented cancer immunotherapy. To construct the hybrids, photothermal nanoparticles responsive to light in the second near-infrared (NIR-II) region are conjugated onto the surface of engineered bacteria through pH-responsive Schiff base bonds. Taking advantage of the hypoxia targeting and deep penetration characteristics of the bacteria, the hybrids can accumulate at tumor sites. Then nanoparticles detach from the bacteria to realize genetic engineering of tumor cells, which induces tumor cell apoptosis and down-regulate the expression of programmed cell death ligand 1 to alleviate immunosuppressive tumor microenvironment. The mild photothermal heating can not only induce tumor-associated antigen release, but also trigger sustainable expression of cytokine interleukin-2. Notably, a synergistic antitumor effect is achieved between the process of p53 transfection and NIR-II light-activated genetic engineering of bacteria. This work proposes a facile strategy for the construction of hybrid system to achieve cascade-augmented cancer immunotherapy.

Lung cancer is a severe challenge to the health care system with intrinsic resistance to first and second-line chemo/radiotherapies. In view of the sterile environment of lung cancer, several immunotherapeutic drugs including nivolumab, pembrolizumab, atezolizumab, and durvalumab are currently being used in clinics globally with the intention of releasing exhausted T-cells back against refractory tumor cells. Immunotherapies have a limited response rate and may cause immune-related adverse events (irAEs) in some patients. Hence, a deeper understanding of regulating immune checkpoint interactions could significantly enhance lung cancer treatments. In this review, we explore the role of miRNAs in modulating immunogenic responses against tumors. We discuss various aspects of how manipulating these checkpoints can bias the immune system's response against lung cancer. Specifically, we examine how altering the miRNA profile can impact the activity of various immune checkpoint inhibitors, focusing on the PD-1/PD-L1 pathway within the complex landscape of lung cancer. We believe that a clear understanding of the host's miRNA profile can influence the efficacy of checkpoint inhibitors and significantly contribute to existing immunotherapies for lung cancer patients. Additionally, we discuss ongoing clinical trials involving immunotherapeutic drugs, both as standalone treatments and in combination with other therapies, intending to advance the development of immunotherapy for lung cancer.

PD-L1 expression on cancer cells is an important mechanism of tumor immune escape, and immunotherapy targeting the PD-L1/PD1 interaction is a common treatment option for patients with melanoma. However, many patients do not respond to treatment and novel predictors of response are emerging. One suggested modifier of PD-L1 is the p53 pathway, although the relationship of p53 pathway function and activation is poorly understood.

The study was performed on human melanoma cell lines with various p53 status. We investigated PD-L1 and proteins involved in IFNγ signaling by immunoblotting and mRNA expression, as well as membrane expression of PD-L1 by flow cytometry. We evaluated differences in the ability of NK cells to recognize and kill target tumor cells on the basis of p53 status. We also investigated the influence of proteasomal degradation and protein half-life, IFNγ signaling and p53 activation on biological outcomes, and performed bioinformatic analysis using available data for melanoma cell lines and melanoma patients.

We demonstrate that p53 status changes the level of membrane and total PD-L1 protein through IRF1 regulation and show that p53 loss influences the recently discovered SOX10/IRF1 regulatory axis. Bioinformatic analysis identified a dependency of SOX10 on p53 status in melanoma, and a co-regulation of immune signaling by both transcription factors. However, IRF1/PD-L1 regulation by p53 activation revealed complicated regulatory mechanisms that alter IRF1 mRNA but not protein levels. IFNγ activation revealed no dramatic differences based on TP53 status, although dual p53 activation and IFNγ treatment confirmed a complex regulatory loop between p53 and the IRF1/PD-L1 axis.

We show that p53 loss influences the level of PD-L1 through IRF1 and SOX10 in an isogenic melanoma cell model, and that p53 loss affects NK-cell cytotoxicity toward tumor cells. Moreover, activation of p53 by MDM2 inhibition has a complex effect on IRF1/PD-L1 activation. These findings indicate that evaluation of p53 status in patients with melanoma will be important for predicting the response to PD-L1 monotherapy and/or dual treatments where p53 pathways participate in the overall response.

Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range of immune-based therapies, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T, and hematopoietic stem cell transplantation (HSCT). This highlights the role of p53 mutations in driving immune evasion of tumor cells. In this review, we first summarize recent studies revealing mechanisms by which p53-mutant tumors evade immune surveillance from T cells, natural killer (NK) cells, and macrophages. We then review how these mutant tumor cells reshape the tumor microenvironment (TME), modulating bystander cells such as macrophages, neutrophils, and regulatory T (Treg) cells to foster immunosuppression. Additionally, we review clinical observations indicative of immune evasion associated with p53 loss or mutations. Finally, we discuss therapeutic strategies to enhance immune response in p53 wild-type (WT) or mutant tumors.

Mutation of thetumor suppressor gene, TP53 (tumor protein 53), occurs in up to 15% of all patients with acute myeloid leukemia (AML) and is enriched within specific clinical subsets, most notably in older adults, and including secondary AML cases arising from preceding myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), patients exposed to prior DNA-damaging, cytotoxic therapies. In all cases, these tumors have remained difficult to effectively treat with conventional therapeutic regimens. Newer approaches fortreatmentofTP53-mutated AML have shifted to interventions that maymodulateTP53 function, target downstream molecular vulnerabilities, target non-p53 dependent molecular pathways, and/or elicit immunogenic responses. This review will describe the basic biology of TP53, the clinical and biological patterns of TP53 within myeloid neoplasms with a focus on elderly AML patients and will summarize newer therapeutic strategies and current clinical trials.

Cellular crosstalk mediated by ligand-receptor interactions largely complicates the tumour ecosystem, resulting in heterogeneous tumour microenvironments that affect immune response and clinical benefits from immunotherapy. Epigenetic mechanisms are pivotal to expression changes of immune-related genes and can modulate the anti-tumour immune response. However, the functional consequences of disrupted epigenetic regulators (ERs) on ligand-receptor interactions in the tumour microenvironment remain largely unexplored. Here, we proposed mutations of ERs in perturbed interactions (MERIN), a molecular network-based approach that incorporates multi-omics data, to infer the potential consequences of ER mutations on ligand-receptor interaction perturbations. Leveraging cancer genomic profiles and molecular interaction data, we comprehensively decoded the functional consequences of ER mutations on dysregulated ligand-receptor interactions across 33 cancers. The dysregulated ligand-receptor genes were indeed enriched in cancer and immune-related function. We demonstrated the potential significance of PD1-PDL1 interaction-related ER mutations in stratifying cancer patients from multiple independent data cohorts. The ER mutation group showed distinct immunological characterizations and prognoses. Furthermore, we highlighted that the ER mutations could potentially predict clinical outcomes of immunotherapy. Our computational and clinical assessment underscore the utility of MERIN for elucidating the functional relevance of ER mutations in cancer immune response, potentially aiding patients' stratification for immunotherapy.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. TP53, which has a mutation rate of ≈70%-80% in TNBC patients, plays oncogenic roles when mutated. However, whether circRNAs can exert their effects on TNBC through regulating mutant TP53 has not been well evaluated. In this study, circCFL1, which is highly expressed in TNBC cells and tissues and has prognostic potential is identified. Functionally, circCFL1 promoted the proliferation, metastasis and stemness of TNBC cells. Mechanistically, circCFL1 acted as a scaffold to enhance the interaction between HDAC1 and c-Myc, further promoting the stability of c-Myc via deacetylation-mediated inhibition of K48-linked ubiquitylation. Stably expressed c-Myc further enhanced the expression of mutp53 in TNBC cells with TP53 mutations by directly binding to the promoter of TP53, which promoted the stemness of TNBC cells via activation of the p-AKT/WIP/YAP/TAZ pathway. Moreover, circCFL1 can facilitate the immune escape of TNBC cells by promoting the expression of PD-L1 and suppressing the antitumor immunity of CD8+ T cells. In conclusion, the results revealed that circCFL1 plays an oncogenic role by promoting the HDAC1/c-Myc/mutp53 axis, which can serve as a potential diagnostic biomarker and therapeutic target for TNBC patients with TP53 mutations.

RNA-binding motif protein 10 (RBM10) has a tumor suppressor role in multiple cancers. Combining Oncomine database results with tissue samples, Western blot analysis showed that RBM10 was significantly lower in lung adenocarcinoma (LUAD) than in adjacent normal tissues. Moreover, KM analysis revealed that the group with higher RBM10 expression in LUAD correlated with better overall survival (OS). Luciferase reporter assay revealed that an important tumor-promotive miRNA, miR-224-5p, was directly bound to the 3'UTR of RBM10, resulting in inhibition of RBM10 expression, and promoted LUAD progression both in vitro and in vivo. Mechanistically, we found that miR-224-5p directly targeted RBM10 to inhibit p53 expression during LUAD progression. Meanwhile, p53 affected RBM10 expression through p53/miR-224-5p axis. Our study identified RBM10 as a key tumor suppressor in the proliferation and metastasis of LUAD. The findings provide a novel mechanism involving a feedback loop of miR-224-5p/RBM10/p53 regulated tumor progression in LUAD, which may help with the design of more effective LUAD treatments.

Melanoma brain metastases present a major challenge in cancer treatment and reduce overall survival despite advances in managing primary melanoma. Immune checkpoint inhibitors (ICIs) that target PD-1/PD-L1 pathways have shown promise in treating advanced melanoma, but their efficacy for melanoma brain metastases is debated. This systematic review and meta-analysis summarize evidence on anti-PD-1/PD-L1 inhibitors for melanoma brain metastases. This systematic review and meta-analysis followed PRISMA guidelines. PICO criteria targeted melanoma brain metastasis patients treated with PD-1/PD-L1 inhibitors, assessing overall survival, progression-free survival, and complications. Inclusion criteria were English studies on humans using PD-1/PD-L1 inhibitors for melanoma brain metastases with > 10 patients. A total of 22 trials involving 1523 melanoma brain metastase patients treated with anti-PD-1/PD-L1 inhibitors were thoroughly analyzed. Our findings show the 6-month OS rate of 0.75 [95%CI:0.67-0.84], the 6-months PFS rate of 0.42 [95%CI:0.31-0.52], the 1-year OS rate of 0.63 [95%CI:0.52-0.74], the 1-year PFS rate was 0.45 [95%CI:0.32-0.58], the 18-months OS rate of 0.52 [95%CI:0.37-0.67], the 2-year OS rate of 50% [95% CI: (34%-65%)], the 2 year PFS rate of 0.36 (95%CI:0.23-0.50), the 3-year OS rate of 0.42 (95%CI:0.17-0.67), the 4-year PFS rate of 0.35 [95%CI:0.08-0.61], the 4-year OS rate of 0.29 [95%CI:0.01-0.56], the 5-year OS rate of 0.29 (95%CI:0.09-0.50), and the 5-year PFS rate of 0.11 (95%CI:0.03-0.19). The combined disease stability rate was 0.13 [95%CI:0.05-0.20], the progressive disease rate was 0.49 [95%CI:0.37-0.62], the partial response rate was 0.14 [95%CI:0.07-0.20], the object response rate was 0.35 [95%CI:0.24-0.46], and the complete response rate was 0.22 [95%CI:0.12-0.32]. In conclusion, our meta-analysis provides compelling evidence supporting the efficacy of PD-1/PD-L1 inhibitors in patients with melanoma brain tumors, as evidenced by favorable survival outcomes and disease control rates.

The tumor suppressor proteins are key transcription factors involved in the regulation of various cellular processes, such as apoptosis, DNA repair, cell cycle, senescence, and metabolism. The tumor suppressor protein p53 responds to different type of stress signaling, such as hypoxia, DNA damage, nutrient deprivation, oncogene activation, by activating or repressing the expression of different genes that target processes mentioned earlier. p53 has the ability to modulate the activity of many other proteins and signaling pathway through protein-protein interaction, post-translational modifications, or non-coding RNAs. In many cancers the p53 is found to be mutated or inactivated, resulting in the loss of its tumor suppressor function and acquisition of new oncogenic properties. The tumor suppressor protein p53 also plays a role in the development of other metabolic disorders such as diabetes, obesity, and fatty liver disease. In this review, we will summarize the current data and knowledge on the molecular mechanisms and the functions of p53 in different pathways and processes at the cellular level and discuss the its implications for human health and disease.