The immune checkpoint inhibitor ipilimumab provides long term survival in some metastatic melanoma patients, but the majority has no benefit, and may experience serious side effects. Here, we investigated the dynamics of plasma cytokine concentrations and their potential utility for predicting treatment response, adverse events and overall survival (OS) in patients with metastatic melanoma undergoing ipilimumab monotherapy. A cohort of 148 patients was examined, with plasma samples collected prior to treatment initiation and at the end of the first and second treatment cycles. Concentrations of 48 plasma proteins were measured using a multiplex immunoassay. The results revealed a general increase in cytokine levels following the first ipilimumab dose, consistent with immune activation. Patients not responding to treatment exhibited significantly elevated baseline levels of G-CSF, IL-2RA, MIP-1a, and SCF, compared to tumor responders (p < 0.05). Furthermore, high levels of IL-2RA, IFNγ, PDGF-bb and MIG were linked to inferior OS, while high concentrations of MIF and RANTES were associated with improved OS (p < 0.05). A multivariate model containing CRP, LDH, ECOG, IL-2RA and PDGF-bb identified a subgroup of patients with poor OS. Patients who experienced severe immune-related adverse events within three months of treatment initiation had higher baseline concentrations of several cytokines, indicating a potential association between preexisting inflammation and adverse events. These findings indicate that the first dose of ipilimumab induces a systemic response with increased levels of circulating cytokines and suggest candidate biomarkers for clinical response, immune-mediated toxicity and survival. Further studies in independent patient cohorts are required to confirm the findings.

Adaptive immune resistance in cancer describes the various mechanisms by which tumors adapt to evade anti-tumor immune responses. IFN-γ induction of programmed death-ligand 1 (PD-L1) was the first defined and validated adaptive immune resistance mechanism. The endoplasmic reticulum (ER) is central to adaptive immune resistance as immune modulatory secreted and integral membrane proteins are dependent on ER. Sigma1 is a unique ligand-regulated integral membrane scaffolding protein enriched in the ER of cancer cells. PD-L1 is an integral membrane glycoprotein that is translated into the ER and processed through the cellular secretory pathway. At the cell surface, PD-L1 is an immune checkpoint molecule that binds PD-1 on activated T-cells and blocks anti-tumor immunity. PD-L1 can also be incorporated into cancer cell-derived extracellular vesicles (EVs), and EV-associated PD-L1 can inactivate T-cells within the tumor microenvironment. Here, we demonstrate that a selective small molecule inhibitor of Sigma1 can block IFN-γ mediated adaptive immune resistance in part by altering the incorporation of PD-L1 into cancer cell-derived EVs. Sigma1 inhibition blocked post-translational maturation of PD-L1 downstream of IFN-γ/STAT1 signaling. Subsequently, EVs released in response to IFN-γ stimulation were significantly less potent suppressors of T-cell activation. These results suggest that by reducing tumor derived immune suppressive EVs, Sigma1 inhibition may promote antitumor immunity. Sigma1 modulation presents a novel approach to regulating the tumor immune microenvironment by altering the content and production of EVs. Altogether, these data support the notion that Sigma1 may play a role in adaptive immune resistance in the tumor microenvironment.

Herein, we firstly reported a series of biphenyl compounds bearing hydroxamic acid moiety as PD-L1/class I HDACs dual inhibitors. Among them, compound 14 displayed the strongest inhibitory activity in vitro against HDAC2 and HDAC3 with IC50 values of 27.98 nM and 14.47 nM, and had an IC50 value of 88.10 nM for PD-1/PD-L1 interaction. Importantly, 14 could upregulate the expression of PD-L1 and CXCL10 in a PD-L1 low-expression cancer cell line (MCF-7), highlighting the potential to enhance efficacy by recruiting T-cell infiltration into TME and improving the response of PD-1/PD-L1 inhibitor associated with PD-L1 low-expression. Besides, we identified another compound, 22, which possessed the strongest inhibitory activity against PD-1/PD-L1 interaction with an IC50 value of 12.47 nM, and effectively inhibited the proliferation of three cancer cell lines. Our results suggest that compounds 14 and 22 can be served as lead compounds of PD-L1/class I HDACs dual inhibitors for further optimisation.

Hepatocellular carcinoma (HCC) recurrence was previously characterized into four types, and patients with progression/hyper-progression recurrence (type III-IV) have an extremely poor prognosis. However, the immune background of resectable HCC, particularly in patients who experience recurrence, remains underexplored. Therefore, this study aimed to describe the immune landscape of resectable HCC, especially postoperative type III-IV recurrent HCC, and explore potential immune-targeted anti-relapse strategies for treated populations.

The differences in gene expression in patients with recurrent HCC (type I-II (solitary or multi-intrahepatic oligo recurrence) vs. type III-IV) were investigated using bulk sequencing. Multiple immune infiltration methods (single-sample gene set enrichment analysis (GSEA), Microenvironment Cell Populations-counter and ESTIMATE) were used, and patients were divided into four groups to identify four distinct immune subtypes: immune-enrichment/matrix-poor (IE1), immune-enrichment/matrix-rich (IE2), immune intermediate/matrix-rich (ITM) and immune desert/matrix-poor (ID). Co-expression and protein interaction analyses were used to identify characteristic genes in ITM closely associated with type III-IV recurrence, which was matched with drug targets for Huaier granules (HG) and lenvatinib. Virtual docking was used to identify potential therapeutic targets, and the results were verified using single-nuclei RNA sequencing and histological analysis.

ITM was closely related to type III-IV recurrence and exhibited immunotherapy potential. The potential efficacy of inhibiting CCNA2, VEGFA, CXCL8, PLK2, TIMP1, ITGB2, ALDOA, ANXA5 and CSK in ITM reversal was determined. Molecular docking demonstrated that the proteins of these genes could bind to HG or lenvatinib. The immunohistochemical findings demonstrated differential VEGFA (p < .01) and PLK2 (p < .001) expression in ITM type and ID in type III-IV recurrent HCC.

Three primary immunotypes of resectable HCC (IE2, ITM and ID) were identified, and HG and lenvatinib could potentially overcome immune checkpoint blockade (ICB) resistance in ITM patients with HCC, particularly those classified as type III-IV.

Rectal adenocarcinoma (READ) involves the dysregulated expression of alpha 2,8-Sialyltransferase1 (ST8Sia1) although its role during READ's progression is unclear.

The mRNA level of ST8Sia1 was analyzed based on The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Tumor Immune Estimation Resource (TIMER) 2.0. Furthermore, the prognostic and significance of ST8Sia1 in READ was assessed through Kaplan-Meier curve, univariate, multivariate Cox regression, and receiver operating characteristic (ROC) methods. The role of ST8Sia1 in the READ immune microenvironment was explored using ESTIMATE analysis and TIMER databases. Furthermore, the expression of ST8Sia1 in tissues was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB), and immunohistochemistry (IHC). Perforin and Granzyme B secretion by CD8+ T cells, as well as tumor cell apoptosis, were detected after co-culturing CD8+ T cells with READ tumor cells and ST8Sia1-overexpression (ST8Sia1-OE) tumor cells. Furthermore, we examined the interaction between ST8Sia1 and TGF-β1 in READ cells.

ST8Sia1 exhibited excellent diagnostic capability for READ, with positive correlations to immune response and negative correlations to tumor purity. Increased levels of perforin and Granzyme B from CD8+ T cells were observed in vitro, enhancing tumor cell apoptosis. ST8Sia1 interacts with TGF-β1, mediating its inhibitory effects on READ development.

ST8Sia1 is a potential diagnostic biomarker and therapeutic target for READ, enhancing CD8+ T cell function and possibly improving patient outcomes through cellular immunotherapy.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with limited treatment options at advanced stages. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a pivotal role in regulating immune responses through the gut-liver axis. Emerging evidence underscores its impact on HCC progression and the efficacy of immunotherapy. This review explores the intricate interactions between gut microbiota and the immune system in HCC, with a focus on key immune cells and pathways involved in tumor immunity. Additionally, it highlights strategies for modulating the gut microbiota - such as fecal microbiota transplantation, dietary interventions, and probiotics - as potential approaches to enhancing immunotherapy outcomes. A deeper understanding of these mechanisms could pave the way for novel therapeutic strategies aimed at improving patient prognosis.

Hindered by the challenges of blood-brain barrier (BBB) hindrance, tumor heterogeneity and immunosuppressive microenvironment, patients with breast cancer brain metastasis have yet to benefit from current clinical treatments, experiencing instead a decline in quality of life due to radiochemotherapy. While virus-mimicking nanosystems (VMN) mimicking viral infection processes show promise in treating peripheral tumors, the inability to modulate the immunosuppressive microenvironment limits the efficacy against brain metastasis. Accordingly, a VMN-based triple immunomodulatory strategy is initially proposed, aiming to activate innate and adaptive immune responses and reverse the immunosuppressive microenvironment. Here, manganese-based virus-mimicking nanomedicine (Vir-HD@HM) with intratumoral drug enrichment is engineered. Vir-HD@HM can induce the immune response through the activation of cGAS-STING by mimicking the in vivo infection process of herpesviruses. Meanwhile, DNAzyme mimicking the genome can rescue the epigenetic silencing of PTEN with the assistance of Mn2+, thus ameliorating the immunosuppressive metastatic microenvironment and achieving synergistic sensitizing therapeutic efficacy. In vivo experiments substantiate the efficacy of Vir-HD@HM in recruiting NK cells and CD8+ T cells to metastatic foci, inhibiting Treg cells infiltration, and prolonging murine survival without adjunctive radiochemotherapy. This study demonstrates that Vir-HD@HM with triple immunomodulation offers an encouraging therapeutic option for patients with brain metastasis.

Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, plays a critical role in negatively regulating T-cell, natural killer (NK) cell, and B-cell activation. Inhibiting Cbl-b has emerged as a promising immuno-oncology strategy to enhance immune cell function. Here, we describe the rational design and optimization of pyrrolo-pyridone derivatives as potent Cbl-b inhibitors. Using structure-based drug design, we identified key structural elements that enhance binding affinity and inhibitory potency. Notably, compound B2 stands out, showing superior potency in stimulating IL-2 production in T cells and modulating phosphorylation of key proteins in T-cell receptor signaling. Furthermore, B2 demonstrates favorable pharmacokinetics and significantly inhibits tumor growth in vivo, outperforming NX-1607, which is currently in clinical trials.

Regulatory T cells (Tregs) are critical for maintaining the stability of the immune system and facilitating tumor escape through various mechanisms. Resting T cells are involved in cell-mediated immunity and remain in a resting state until stimulated, while effector T cells promote immune responses. Here, we investigated the roles of two gene signatures, one for resting Tregs (FOXP3 and IL2RA) and another for effector Tregs (FOXP3, CTLA-4, CCR8 and TNFRSF9) in pan-cancer. Using data from The Cancer Genome Atlas (TCGA), The Cancer Proteome Atlas (TCPA) and Gene Expression Omnibus (GEO), we focused on the expression profile of the two signatures, the existence of single nucleotide variants (SNVs) and copy number variants (CNVs), methylation, infiltration of immune cells in the tumor and sensitivity to different drugs. Our analysis revealed that both signatures are differentially expressed across different cancer types, and correlate with patient survival. Furthermore, both types of Tregs influence important pathways in cancer development and progression, like apoptosis, epithelial-to-mesenchymal transition (EMT) and the DNA damage pathway. Moreover, a positive correlation was highlighted between the expression of gene markers in both resting and effector Tregs and immune cell infiltration in adrenocortical carcinoma, while mutations in both signatures correlated with enrichment of specific immune cells, mainly in skin melanoma and endometrial cancer. In addition, we reveal the existence of widespread CNVs and hypomethylation affecting both Treg signatures in most cancer types. Last, we identified a few correlations between the expression of CCR8 and TNFRSF9 and sensitivity to several drugs, including COL-3, Chlorambucil and GSK1070916, in pan-cancer. Overall, these findings highlight new evidence that both Treg signatures are crucial regulators of cancer progression, providing potential clinical outcomes for cancer therapy.

PD-L1 expression in prostate cancer (PCa) is a complex phenomenon, and its clinical utility is debated. While it is a potential target for immunotherapy, interpreting PD-L1 scores remains unstandardized, and its role in guiding treatment decisions is unclear. Our study aimed to investigate the relationship between PD-L1 expression (measured by Combined Positive Score, CPS) and PCa aggressiveness (indicated by Gleason Grade Groups [GGs]).

A retrospective analysis of 120 prostate biopsies from 52 PCa patients was conducted. PD-L1 CPS was assessed and the correlation between CPS and GGs was statistically analyzed.

A non-linear correlation was observed between CPS positivity and increasing GG, with the highest proportion in GG2 and GG5. Notably, GG5 exhibited the highest PD- L1 expression. However, PD-L1 expression varied within patients, indicating heterogeneity. Despite the non-linear correlation, statistical analyses confirmed a positive association overall, with higher GGs generally showing increased CPS values. A one-way ANOVA demonstrated a statistically significant difference in mean CPS values across the different GGs (p < 0.0001) and linear regression analysis further confirmed a direct correlation between PD-L1 values and GG (p < 0.0001). A significant association was also observed between cribriform morphology and CPS ≥ 1. Additionally, patients with CPS ≥ 1 had a shorter biochemical recurrence (BCR)-free survival.

Our study highlights a positive correlation between PD-L1 expression and GG in PCa, suggesting that higher PD-L1 expression is linked to more aggressive disease. This finding could have implications for treatment selection and the use of immunotherapy, particularly for patients with higher GGs.

Regulatory T cells can suppress activated T-cell proliferation by direct cell contact, although the exact mechanism is poorly understood. Identification of a Treg-specific cell surface molecule that mediates suppression would offer a unique target for cancer immunotherapy to inhibit Treg immunosuppressive function or deplete Tregs in the tumor microenvironment. In this study, we explored a method of whole-cell immunization using a Treg-like cell line (MoT cells) to generate and screen monoclonal antibodies that bound cell surface proteins in their native conformations and functionally reversed Treg-mediated suppression. From the 105 hybridomas that bound to the MoT cell surface, a functional screen utilizing conventional Treg suppression assays revealed 32 candidate antibodies that exhibited functional activity (reversed or enhanced suppressive activity). As an example, we characterized 1 anti-MoT mAb, 12E7, that exhibited strong binding to MoT cells and conventional Treg cell surfaces. This candidate antibody was subsequently found to bind to a potential suppressive target, CD44, and demonstrated the ability to partially reverse MoT and conventional human Treg-mediated suppression.

Blockade of immune checkpoints, such as programmed death-ligand 1 (PD-L1), has shown promise in cancer treatment; however, clinical response remains limited in many cancer types. Our previous research demonstrated that p300/CBP mediates the acetylation of the PD-L1 promoter, regulating PD-L1 expression. In this study, we further investigated the role of the p300/CBP bromodomain in regulating PD-L1 expression using CCS1477, a selective bromodomain inhibitor developed by our team. We found that the p300/CBP bromodomain is essential for H3K27 acetylation at PD-L1 enhancers. Inhibiting this modification significantly reduced enhancer activity and PD-L1 transcription, including exosomal PD-L1, which has been implicated as key contributors to resistance against PD-L1 blockade therapy in various cancers. Furthermore, CCS1477 treatment resulted in a marked reduction of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) by inhibiting key cytokines such as IL6, CSF1, and CSF2, which are crucial for MDSC differentiation and recruitment. By reducing PD-L1 expression and modulating the immunosuppressive TME, CCS1477 creates a more favorable environment for tumor-infiltrating lymphocytes, significantly enhancing the efficacy of immune checkpoint blockade (ICB) therapy. Notably, these effects were observed in both prostate cancer and melanoma models, underscoring the broad therapeutic potential of p300/CBP bromodomain inhibition in improving ICB outcomes.

Gastric cancer is one of the major health threats to human beings and has a low response rate to emerging immunotherapy. We herein reported a novel indole-based LSD1-targeted antigastric agent 7ae, which was able to enhance the sensitivity of gastric cancer cells to a T-cell-mediated immune response. It exhibited potent LSD1 inhibitory activity (IC50 = 0.080 ± 0.002 μM) and reduced the expression of PD-L1, which in turn promoted the T-cell killing response in gastric cancer cells. As a result, 7ae acted as an active LSD1 inhibitor, exerting excellent anti-invasion and anti-migration effects in gastric cancer cells and leading to significant suppression of the growth of xenograft gastric tumors without obvious toxicity in vivo. Collectively, 7ae has been demonstrated to be a novel, potent LSD1 inhibitor with the potential to be used as an antigastric agent, as well as a useful tool compound for exploratory studies of T-cell-mediated immunity and/or immunotherapy in gastric cancer.

PD-L1, an immune checkpoint inhibitor, and VEGFR2, essential for cancer metastasis, play pivotal roles in tumorigenesis. However, their miniature bispecific intracellular nanobodies for combining check-point blockade and anti-metastasis anticancer therapy remain underexplored.

The intrabodies were developed using gene cloning technology. Specificity of the intrabodies was testified using Western blot, co-immunoprecipitation (co-IP) analysis, antibody competitive binding assay, flow cytometry analysis, etc. Checkpoint blockade was demonstrated using antibody-antigen competitive binding assay. Cancer cell migration was determined using scratch assay. Combined anti-cancer therapeutic efficacy of FAP1V2 was determined in vivo of mice models. The PD-1hi immune cells, TCR βhi and CD25hi T-cells were analyzed by flow cytometry, and cancer cell metastasis was performed using immune-fluorescence analysis on lung and liver tissues. Transcriptome analysis was performed to explore signaling pathways associated with the enhanced anticancer efficiency.

Bispecific intrabody FAP1V2 fused with antibody VH regions, was successfully developed and verified with its ability to target and block human and mouse PD-L1 and VEGFR2, inhibiting cancer cell binding to PD-1 and reducing their migratory capacity. Compared to the other treatment, two-rounds of transient FAP1V2 expression in LLC cells in experimental mice models achieved remarkable tumor inhibition, which brought about complete immune inhibition on growth of secondary-round of LLC tumor in 1/6 of the tested mice, inspired long-term activation of TCR βhi T cells and increased their infiltration to tumors, inhibited the emergence of PD-1hi immune cells, indicating prevented T cell depletion. The elevated CD25 expression also supported the success in enhancing immune response reported by elevated T cell activity in spleen. Transcriptome analysis identified critical intracellular pathways regulated by the concurrent blockade of PD-L1 and VEGFR2.

PD-L1 and VEGFR2- bispecific VH intracellular nanobody was highly biocompatible and showed the potential for combined anti-cancer therapy through long-term immune activation mediated by PD-L1/PD-1 checkpoint blockade and anti-metastasis mediated by VEGFR2 blockade.

The relationship between circulating tumor cells (CTCs) and patients with advanced gallbladder adenocarcinoma (aGA) has been rarely studied. This article was to demonstrate the enumeration, classification, and clinical application of CTCs in patients with aGA.

Peripheral blood samples were collected and CTCs were detected using the CanPatrol® technique. T test, χ2 test, Wilcoxon rank sum test or Kruskal-Wallis test, log-rank test and Cox regression analysis were performed to conduct statistical analysis.

CTCs were detected at pre-treatment in 75.00% (27/36) of the patients. Both CTCs positive rate and CTCs enumeration at pre-treatment were significantly associated with clinicopathological parameters including Ca199 level (P = 0.014, P < 0.001 respectively), tumor differentiation (P = 0.007, P = 0.002 respectively), lymph infiltration (P = 0.010, P = 0.025 respectively), vascular infiltration (P = 0.007, P < 0.001 respectively), and distant metastasis (P = 0.015, P = 0.002 respectively). CTCs-positive patients had a significantly shorter OS (HR 0.335, 95% CI 0.165-0.678, P = 0.0023) and PFS (HR 0.364, 95% CI 0.179-0.739, P = 0.0024) than CTCs-negative patients. Mesenchymal CTCs enumeration was closely related to the chemotherapy response, and CTCs programmed cell death ligand-1 (PD-L1) was highly correlated with the immunotherapy response. Positive CTCs at pre-treatment was closely related to the poor OS (HR 0.089, 95% CI 0.020-0.399, P = 0.002) as well as distant metastasis (HR 0.159, 95% CI 0.041-0.610, P = 0.007), untreated with chemotherapy (HR 4.510, 95% CI 1.403-14.499, P = 0.011) and untreated with immunotherapy (HR 6.845, 95% CI 1.894-24.738, P = 0.003).

Pretreatment-positive CTCs was closely related to the poor prognosis in patients with aGA. Monitoring the subtype and phenotype of CTCs may be one of the means to assess tumor treatment response.

Cancer is one of the leading causes of mortality worldwide. Nanomedicines have significantly improved life expectancy and survival rates for cancer patients in current standard care. However, recurrence of cancer due to metastasis remains a significant challenge. Vaccines can provide long-term protection and are ideal for preventing bacterial and viral infections. Cancer vaccines, however, have shown limited therapeutic efficacy and raised safety concerns despite extensive research. Cancer vaccines target and stimulate responses against tumor-specific antigens and have demonstrated great potential for cancer treatment in preclinical studies. However, tumor-associated immunosuppression and immune tolerance driven by immunoediting pose significant challenges for vaccine design. In situ vaccination represents an alternative approach to traditional cancer vaccines. This strategy involves the intratumoral administration of immunostimulants to modulate the growth and differentiation of innate immune cells, such as dendritic cells, macrophages, and neutrophils, and restore T-cell activity. Currently approved in situ vaccines, such as T-VEC, have demonstrated clinical promise, while ongoing clinical trials continue to explore novel strategies for broader efficacy. Despite these advancements, failures in vaccine research highlight the need to address tumor-associated immune suppression and immune escape mechanisms. In situ vaccination strategies combine innate and adaptive immune stimulation, leveraging tumor-associated antigens to activate dendritic cells and cross-prime CD8+ T cells. Various vaccine modalities, such as nucleotide-based vaccines (e.g., RNA and DNA vaccines), peptide-based vaccines, and cell-based vaccines (including dendritic, T-cell, and B-cell approaches), show significant potential. Plant-based viral approaches, including cowpea mosaic virus and Newcastle disease virus, further expand the toolkit for in situ vaccination. Therapeutic modalities such as chemotherapy, radiation, photodynamic therapy, photothermal therapy, and Checkpoint blockade inhibitors contribute to enhanced antigen presentation and immune activation. Adjuvants like CpG-ODN and PRR agonists further enhance immune modulation and vaccine efficacy. The advantages of in situ vaccination include patient specificity, personalization, minimized antigen immune escape, and reduced logistical costs. However, significant barriers such as tumor heterogeneity, immune evasion, and logistical challenges remain. This review explores strategies for developing potent cancer vaccines, examines ongoing clinical trials, evaluates immune stimulation methods, and discusses prospects for advancing in situ cancer vaccination.

Sialic acid-binding immunoglobulin-like lectin (Siglec)-15-expressing tumor-associated macrophages (TAMs) drive immunosuppression in the tumor microenvironment (TME), promoting CD8+ T cell exhaustion and limiting immunotherapy efficacy. Both blockade of immune checkpoint molecule Siglec-15 and promotion of granulocyte-macrophage colony-stimulating factor (GM-CSF) have been respectively employed in anticancer immunotherapy.

Murine CT26 or MC38 cancer cells were used to establish subcutaneous tumor models in BALB/c or C57BL/6 mice. Tumors were treated with anti-Siglec-15 antibody-GM-CSF chimera (anti-S15×GM CSF) or anti-Siglec-15 antibody via intraperitoneal injection. The TME was analyzed by flow cytometry and ELISA for immune cell infiltration and cytokine levels. Biodistribution and half-life of anti-S15×GM CSF were assessed by intravenous injection in tumor-bearing mice, with GM-CSF levels measured by ELISA. Macrophage reprogramming and antigen presentation were evaluated using bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages treated with anti-S15×GM CSF, followed by flow cytometry and immunofluorescence assays.

Here we report that anti-S15×GM CSF displays superior function to suppress the progression of Siglec-15-overexpressing MC38 colon cancer engrafted in mice compared to anti-Siglec-15 antibody or GM-CSF alone. Different from the injected GM-CSF which is distributed broadly in various organs and tissues of mouse, the injected anti-S15×GM CSF is preferentially accumulated in Siglec-15-positive tumor cells and TAMs. Anti-S15×GM CSF not only extends the half-life of GM-CSF in vivo, but also reduces the off-target effect of GM-CSF through TAM-specific delivery. In addition to Siglec-15 blockade, anti-S15×GM CSF effectively reprograms immunosuppressive TAMs to a proinflammatory phenotype, enhancing antigen presentation by macrophages to activate T cells.

In summary, our results reveal that anti-S15×GM CSF may serve as an effective therapeutic approach for solid tumors.

The engineerability of lipid nanoparticles (LNPs) and their ability to deliver nucleic acids make LNPs attractive tools for cancer immunotherapy. LNP-based gene delivery can be employed for various approaches in cancer immunotherapy, including encoding tumor-associated antigens and silencing of negative immune checkpoint proteins. For example, LNPs carrying small interfering RNAs can offer several advantages, including sustained and durable inhibition of an immune checkpoint protein. Due to their tunable design, modifying the lipid composition of LNPs can regulate the rate of their uptake by immune cells and the rate of gene silencing. Controlling the kinetics of LNP uptake provides additional flexibility and strategies to generate appropriate immunomodulation in the tumor microenvironment. Here, we evaluated the effects of polyethylene glycol (PEG) content ranging from 0.5 to 6 mol % on the cellular uptake of LNPs by immune cells and gene silencing of PD-L1 after intratumoral administration. We evaluated the cellular uptake and PD-L1 blockade in vitro in cell studies and in vivo using the YUMM1.7 melanoma tumor model. Cell studies showed that the rate of cell uptake was inversely correlated to an increasing mol % of PEG in a linear relationship. In the in vivo studies, 0.5% PEG LNP initiated an immediate effect in the tumor with a significant decrease in the PD-L1 expression of immune cells observed within 24 h. In comparison, the gene silencing effect of 6% PEG LNP was delayed, with a significant decrease of PD-L1 expression in immune cell subsets being observed 72 h after administration. Notably, performance of the 6% PEG LNP at 72 h was comparable to that of the 0.5% PEG LNP at 24 h. Overall, this study suggests that PEG modifications and intratumoral administration of LNPs can be a promising strategy for an effective antitumor immune response.

This retrospective study aims to evaluate the impact of antibiotics (ATBs) use on the efficacy of immunotherapy in patients with advanced hepatocellular carcinoma (HCC), providing insights into the prudent use of ATBs in patients undergoing immunotherapy.

We retrospectively collected data from patients with advanced HCC treated with immune checkpoint inhibitors (ICIs) at our institution between January 1, 2021, and December 30, 2023. Patients were divided into two groups based on ATBs use: an ATB group and a non-ATB group. Clinical baseline characteristics were analyzed, and survival curves were plotted using the Kaplan-Meier model. A Cox proportional hazards model was employed to analyze influencing factors.

Among the 102 advanced HCC patients receiving ICIs treatment, 29 were in the ATB group, and 73 were in the non-ATB group. The progression-free survival (PFS) (P = 0.034) and overall survival (OS) (P = 0.021) were significantly shorter in the ATB group compared to the non-ATB group. The difference in PFS between the two groups was associated with ATBs use and patients' AFP levels, while ATBs use was identified as an independent risk factor for the difference in OS between the groups.

ATB use in the context of immunotherapy for advanced HCC is associated with reduced PFS and OS. Caution is warranted in the administration of ATBs to patients undergoing immunotherapy.

Immunotherapy holds great promise in the fight against cancer; however, it often encounters poor immunogenicity with limited therapeutic efficacy. Combining multiple treatment modalities provides a trustworthy strategy for achieving a robust antitumor effect. In this study, a nucleic acid-locked smart carrier (NASC) is developed to amplify immunogenic cell death (ICD) through the synergistic integration of photothermal therapy (PTT) and chemotherapy for high-performance monotherapy. Mesoporous silica-coated gold nanorod (MSGNR) serves as the reservoir for anticancer drug doxorubicin (DOX) and is capped with a sequence-specific duplex unit containing a tumor-specific targeting AS1411 fragment, resulting in the formation of NASC. With AS1411 targeting, the NASC can specifically target and be internalized into tumor cells with high expression of nucleolin, where the duplex capping can be unlocked by the intracellularly overexpressed adenosine triphosphate. Subsequently, the released DOX synergized with MSGNR-mediated PTT following laser irradiation induces direct cell killing, which, concurrently, triggers ICD to activate antineoplastic immunity with an increased number of T lymphocytes. This triple-collaborative strategy, further combined with anti-programmed death-1 antibody (αPD-1)-mediated immune checkpoint blockade (ICB) therapy, shows a robust therapeutic efficacy in both unilateral and bilateral tumor models.

Stem cells have emerged as a pivotal area of research in the field of oncology, offering new insights into the mechanisms of cancer initiation, progression, and resistance to therapy. This review provides a comprehensive overview of the role of stem cells in cancer, focusing on cancer stem cells (CSCs), their characteristics, and their implications for cancer therapy. We discuss the origin and identification of CSCs, their role in tumorigenesis, metastasis, and drug resistance, and the potential therapeutic strategies targeting CSCs. Additionally, we explore the use of normal stem cells in cancer therapy, focusing on their role in tissue regeneration and their use as delivery vehicles for anticancer agents. Finally, we highlight the challenges and future directions in stem cell research in cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and poor prognosis. The gut microbiota, a diverse community of microorganisms in the gastrointestinal tract, plays a crucial role in regulating immune responses through the gut-immune axis. Recent studies have highlighted its significant impact on TNBC progression and the efficacy of immunotherapies. This review examines the interactions between gut microbiota and the immune system in TNBC, focusing on key immune cells and pathways involved in tumor immunity. It also explores microbiota modulation strategies, including probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation, as potential methods to enhance immunotherapeutic outcomes. Understanding these mechanisms offers promising avenues for improving treatment efficacy and patient prognosis in TNBC.

Pyroptosis has emerged as a promising approach for cancer immunotherapy. However, current pyroptosis inducers lack specificity for cancer cells and have a weak antitumour immune response. Here we report a tumour-specific nanoparticle (NP-NH-D5) that activates pyroptosis by disrupting lysosomes for cancer immunotherapy. NP-NH-D5 undergoes negative-to-positive charge reversal and nanoparticle-to-nanofibre transformation within tumour cell lysosomes through tandem response to extracellular matrix metallopeptidase-2 and intracellular reducing agents. The as-formed non-peptide nanofibres efficiently break the lysosomes and trigger gasdermin-D-mediated pyroptosis, leading to strong immunogenic cell death and alleviation of the immunosuppressive tumour microenvironment. In vivo, NP-NH-D5 inhibits orthotopic 4T1 breast tumours, prevents metastasis and recurrence, and prolongs survival without systemic side effects. Furthermore, it greatly enhances the effectiveness of PD-L1 antibody immunotherapy in the 4T1 late-stage lung metastasis and aggressive orthotopic Pan02 pancreatic tumour models. Our research may open pathways for developing stimuli-responsive pyroptosis inducers for precise cancer immunotherapy.

Targeting immune checkpoint proteins (ICPs) via small molecules open a new window for cancer immunotherapy. Herein, we summarize recent advances of small molecules with novel chemical structures targeting ICPs, discusses their anti-tumor efficacies, which are important for the development of novel small molecules for cancer immunotherapy.

In this review, the latest patents and literature were gathered through the comprehensive searches in the databases of European Patent Office (EPO), Cortellis Drug Discovery Intelligence (CDDI), PubMed and Web of Science using ICPs and compounds as key words.

To develop novel weapons to fight against cancer, small molecules targeting ICPs including CTLA-4, LAG-3, PD-L1, Siglec-9, TIM-3, TIGIT, and VISTA have been synthesized and evaluated in succession. Chief among them are the small molecules targeting PD-L1, which have been intensively investigated in recent years. Various in vitro assays such as ALPHA, HTRF binding assay, NFAT assay have been successfully developed to screen novel IPCs inhibitors. However, the in vivo assay, for example, using double-humanized PD-1/PD-L1 (hPD-1/hPD-L1) mouse as evaluation model, are seldom reported. Novel pharmacophores with new working mechanisms such as proteolysis targeting chimeras (PROTACs) and peptides are needed to enhance the therapeutic efficacy.

To evaluate the performance of MRI-based radiomics in predicting endometrial cancer (EC) with a high tumor mutation burden (TMB-H).

A total of 122 patients with pathologically confirmed EC (40 TMB-H, 82 non-TMB-H) were included in this retrospective study. Patients were randomly divided into training and testing cohorts in a ratio of 7:3. Radiomics features were extracted from sagittal T2-weighted images and contrast-enhanced T1-weighted images. Then, the logistic regression (LR), random forest (RF), and support vector machine (SVM) algorithms were used to construct radiomics models. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the diagnostic performance of each model, and decision curve analysis was used to determine their clinical application value.

Four radiomics features were selected to build the radiomics models. The three models had similar performance, achieving 0.771 (LR), 0.892 (RF), and 0.738 (SVM) in the training cohort, and 0.787 (LR), 0.798 (RF), and 0.777 (SVM) in the testing cohort. The decision curve demonstrated the good clinical application value of the LR model.

The MRI-based radiomics models demonstrated moderate predictive ability for TMB-H EC and thus may be a tool for preoperative, noninvasive prediction of TMB-H EC.

Photo-immunotherapy is one of the most promising cancer treatment strategies. As immunotherapeutic agents, immune checkpoint blockade antibodies against programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) exhibit substantial potential, but have to face non-specific distribution and the subsequent immune-related adverse events. Meanwhile, high-performance phototheranostic agents concurrently possessing multiple phototheranostic modalities and high light-harvesting capacity are really attractive and highly desired as touching phototheranostic modules. Herein, a win-win strategy that integrates phototheranostic molecule design and targeted immunotherapeutic module preparation is developed to construct high-powered photo-immunotherapy systems. Specifically, the phototheranostic agent (AOTTIT) displaying typical aggregation-induced fluorescence extending to the second near-infrared II window, as well as outstanding reactive oxygen species and heat production capacity is first obtained via ingenious design. Notably, AOTTIT exhibits a record high molar extinction coefficient among the reported organic multimodal phototheranostic molecules. Meanwhile, PD-1 genetically engineered cancer cell membrane-derived nanovesicles (PD-1/CMNVs) are prepared as both nanocarriers and immunotherapeutic agents to camouflage AOTTIT nanoparticles, yielding a multifunctional photo-immunotherapeutic agent (CMNPs/PD-1) with tumor-specific active and homologous targeting ability. The distinct suppression of primary and metastatic lung tumors after only once treatment to the primary tumor substantiated the synergistically strengthened photo-immunotherapeutic efficiency of this win-win strategy.

Increasing evidence has showed that tumorigenesis is closely linked to inflammation, regulated by multiple signaling pathways. Among these, the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) axis plays a crucial role in the progression of both inflammation and cancer. Inhibiting the activity of COX-2 can reduce PGE2 secretion, thereby suppressing tumor growth. Therefore, COX-2 inhibitors are considered potential therapeutic agents for cancers. However, their clinical applications are greatly hindered by poor physicochemical properties and serious adverse effects. Fortunately, the advent of nanotechnology offers solutions to these limitations, enhancing drug delivery efficiency and mitigating adverse effects. Given the considerable progress in this area, it is timely to review emerging COX-2 inhibitors-based nanotherapeutics for cancer diagnosis and therapy. In this review, we first outline the various antineoplastic mechanisms of COX-2 inhibitors, then comprehensively summarize COX-2 inhibitors-based nanotherapeutics for cancer monotherapy, combination therapy, and diagnosis. Finally, we highlight and discuss future perspectives and challenges in the development of COX-2 inhibitors-based nanomedicine.

Immune checkpoint blockade (ICB) therapy is a widely favored anti-tumor treatment, but it shows limited response to non-immunogenic "cold" tumors and suffers from drug resistance. Photodynamic therapy (PDT), as a powerful localized treatment approach, can convert a "cold tumor" into a "hot tumor" by inducing immunogenic cell death (ICD) in tumor cells, thereby enhancing tumor immunogenicity and promoting tumor immunotherapy. However, the effectiveness of PDT is largely hindered by the limited penetration depth into tumor tissues. To address these issues, we proposed an all-in-one drug system with NIR-II photo-accelerated PDT effects, efficient immune checkpoint gene silencing, and a facile manufacturing process. The so-called all-in-one drug system comprises a multi-modal designed polymer PPNP and siRNA. PPNP is an amphipathic polymer that includes the near infrared-II (NIR-II) photosensitizer Aza-boron-dipyrromethene (Aza-BODIPY), a glutathione (GSH)-cleavable linker, and a cationic monomer derived from cholesterol. PPNP can self-assemble and efficiently load siRNA. Under laser irradiation, PPNP triggers a potent ICD cascade, causing the on-demand release of siPD-L1, reshaping the tumor's immunosuppressive microenvironment, effectively inhibiting the growth of various tumors, and stimulating the immune memory. This study represents a generalized platform for PDT and gene silencing, designed to modulate immune-related signaling pathways for improved anticancer therapy.

Angiogenesis provides essential nutrients and oxygen to tumors during tumorigenesis, facilitating invasion and metastasis. Consequently, inhibiting tumor angiogenesis is an established strategy in anti-cancer therapy. In this study, we engineered a dual-function nanosystem with both antiangiogenic and photodynamic properties. We transformed the hydrophobic photosensitizer zinc phthalocyanine (PS) into a hydrophilic form via protein renaturation, resulting in a novel photosensitizer: Monocyte-Activating Polypeptide-II (EMAP-II:PS@NPs). Characterization through dynamic light scattering (DLS) and UV-vis spectroscopy showed that these nanoparticles exhibited uniform size and stability, and enhanced solubility. We further demonstrated that EMAP-II:PS@NPs effectively target tumor vascular endothelia causing intracellular photodynamic cytotoxicity. Notably, EMAP-II:PS@NPs achieved effective ablation of solid tumors at significantly reduced dosages of drugs compared to conventional therapies, due to their potent apoptotic effects on light-exposed cells. This study highlights the potential of combining anti-angiogenic activity with phototherapy, paving the way for innovative cancer treatment strategies.

Colorectal cancer (CRC) is one of the most prevalent and lethal cancers worldwide, ranking third in incidence and second in mortality. While immunotherapy has shown promise in patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), its effectiveness in proficient mismatch repair (pMMR) or microsatellite stable (MSS) CRC remains limited. Recent advances highlight the gut microbiota as a potential modulator of anti-tumor immunity. The gut microbiome can significantly influence the efficacy of immune checkpoint inhibitors (ICIs), especially in pMMR/MSS CRC, by modulating immune responses and systemic inflammation. This review explores the role of the gut microbiota in pMMR/MSS CRC, the mechanisms by which it may enhance immunotherapy, and current strategies for microbiota modulation. We discuss the potential benefits of combining microbiota-targeting interventions with immunotherapy to improve treatment outcomes for pMMR/MSS CRC patients.

Colorectal cancer is a prevalent and deadly malignancy globally, posing an important challenge due to its heterogeneity and treatment resistance. Although oral contraceptives have been shown to reduce the incidence of colorectal cancer, their impact on the anti-tumor effect of CD8+ T cells remains unclear. Here we show that the contraceptive Marvelon plays an important role in anti-MC38 tumor immunity. The contraceptive Marvelon significantly inhibits MC38 tumor growth in vivo. Marvelon treatment promotes IFN-γ expression in CD8+ tumor infiltrating lymphocytes, but shows dispensable impact on their exhausted profile. By further investigating the effects of Marvelon's primary components, Ethinylestradiol and Desogestrel, we reveal that Ethinylestradiol enhances IFN-γ production in Type 1 Cytotoxic T (Tc1) cells and significantly inhibits the viability of MC38 tumor cells, whereas Desogestrel exhibits minimal effects. This study not only redefines the role of oral contraceptives but also provides valuable insights for the development of novel immunotherapeutic strategies.

Periodontal pathogen Porphyromonas gingivalis (P. gingivalis) is believed to possess immune evasion capabilities, but it remains unclear whether this immune evasion is related to host gene alternative splicing (AS). In this study, RNA-sequencing revealed significant changes in both AS landscape and transcriptomic profile of macrophages following P. gingivalis infection with/without knockout of gingipain (a unique toxic protease of P. gingivalis). P. gingivalis infection increased the PD-L1 transcripts expression and selectively upregulated a specific coding isoform that more effectively binds to PD-1 on T cells, thereby inhibiting immune function. Biological experiments also detected AS switch of PD-L1 in P. gingivalis-infected or gingipain-treated macrophages. AlphaFold 3 predictions indicated that the protein docking compatibility between PD-1 and P. gingivalis-upregulated PD-L1 isoform was over 80% higher than another coding isoform. These findings suggest that P. gingivalis employs gingipain to modulate the AS of PD-L1, facilitating immune evasion.

The immunotherapy targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death ligand-1 (PD-L1) has achieved significant breakthroughs, but further improvements are still needed in cancer treatment.

We investigated orlistat, a drug approved by the Food and Drug Administration for the treatment of obesity and found that it can enhance the efficacy of CTLA-4 blockade immunotherapy. We conducted both in vivo and in vitro experiments to explore the mechanism by which orlistat increased antitumor immunity.

Orlistat enhances the efficacy of anti-CTLA-4 immunotherapy by suppressing tumor cell PD-L1 protein expression and boosting the transcription of interferon-stimulated genes (ISGs) and MHC-I. Mechanistically, orlistat inhibits AKT activity and subsequent phosphorylation of forkhead box O3a (FOXO3a) at its threonine (T) 32, serine (S) 253, thereby downregulating Forkhead box M1 (FOXM1) expression, which ultimately suppresses PD-L1 transcription. Specifically, inhibition of FOXM1 leads to FOXO3a accumulation through impaired AKT activity. FOXM1 activates protein kinase B (AKT) via acting as a scaffold to facilitate 3-phosphoinositide-dependent protein kinase 1 (PDK1) and AKT and interaction. In addition, orlistat enhances phosphorylated signal transducer and activator of transcription 1 (p-STAT1) at tyrosine (Y) 701, resulting in upregulation of ISGs and MHC-I.

Orlistat plays a crucial role in modulating the immune response and supporting the combination with CTLA-4 blockade to promote antitumor immunotherapy.

The therapeutic efficacy of immune checkpoint blockade (ICB) is critically compromised by inadequate T lymphocyte infiltration, low T cell-induced pro-inflammatory responses, and the accumulation of immunosuppressive cells within the tumor microenvironment (TME). In this work, a chimeric peptide-engineered immunomodulatory nanomedicine (designated as CXNP-CeBM) is developed for photodynamic amplified ICB therapy against breast cancer. CXNP-CeBM is composed of a CXCR4-targeting peptide ((C16)2-KLGASWHRPDK) loaded with the photosensitizer of Ce6 and the PD-1/PD-L1 inhibitor of BMS8. CXNP-CeBM specifically recognizes CXCR4 on breast cancer, thus suppressing CXCR4-mediated signaling pathways and enhancing the intracellular delivery of therapeutic agents. The photodynamic therapy (PDT) of CXNP-CeBM damages primary tumor cells to initiate immunogenic cell death (ICD), leading to the release of high mobility group box 1 (HMGB1) and the exposure of calreticulin (CRT). Simultaneously, the interruption of CXCR4 signaling reduces tumor fibrosis, promotes T-cell infiltration, and decreases the number of immunosuppressive cells, thereby enhancing the immunotherapeutic effect of ICB. Treatment with CXNP-CeBM would activate systemic anti-tumor immunity, leading to effective inhibition of both primary and lung metastatic tumors, while maintaining low systemic toxicity. This work provides a reliable strategy for the delivery of multi-synergistic agents, effectively activating breast cancer immunity through a multifaceted mechanism. STATEMENT OF SIGNIFICANCE: Although immune checkpoint blockade (ICB) has shown great potential for malignant tumor therapy, its efficacy is compromised by immunosuppressive microenvironments. Herein, a CXCR4-targeted immunomodulatory nanomedicine (CXNP-CeBM) was constructed for photodynamic amplified ICB therapy of breast cancer. CXNP-CeBM could selectively deliver photosensitizers and PD-1/PD-L1 inhibitors to breast cancer cells that overexpressed the chemokine receptor CXCR4, while interrupting CXCR4 signaling to reduce tumor fibrosis, promote T-cell infiltration, and decrease the number of immunosuppressive cells. Moreover, CXNP-CeBM induced photodynamic therapy to trigger immunogenic cell death while downregulating the PD-L1 level to destroy immune evasion mechanisms, thus activating immunological cascades to treat both primary and lung metastatic tumors. This study provided a multi-synergistic strategy for breast cancer immunotherapy through a multifaceted mechanism.

Understanding the modulation of specific immune cells within the tumor microenvironment (TME) offers new hope in cancer treatments, especially in cancer immunotherapies. In recent years, immune modulation and resistance to immunotherapy have become critical challenges in cancer treatments. However, novel strategies for immune modulation have emerged as promising approaches for oncology due to the vital roles of the immunomodulators in regulating tumor progression and metastasis and modulating immunological responses to standard of care in cancer treatments. With the progress in immuno-oncology, a growing number of novel immunomodulators and mechanisms are being uncovered, offering the potential for enhanced clinical immunotherapy in the near future. Thus, gaining a comprehensive understanding of the broader context is essential. Herein, we particularly summarize the paradoxical role of tumor-related immune cells, focusing on how targeted immune cells and their actions are modulated by immunotherapies to overcome immunotherapeutic resistance in tumor cells. We also highlight the molecular mechanisms employed by tumors to evade the long-term effects of immunotherapeutic agents, rendering them ineffective.