Tumor cellular senescence, characterized by reversible cell cycle arrest following anti-cancer therapies, presents a complex paradigm in oncology. Given that senescent tumor cells may promote angiogenesis, tumorigenesis, and metastasis, selective killing senescent cells (SCs)-a strategy termed senotherapy-has emerged as a promising approach to improve cancer treatment. However, the clinical implementation of senotherapy faces significant hurdles, including lack of precise methods for SCs identification and the potential for adverse effects associated with highly cytotoxic senolytic agents. In this account, we elucidate recent advancement in developing novel approaches for the detection and selective elimination of SCs, encompassing prodrugs, nanoparticles, and other cutting-edge drug delivery systems such as PROTAC technology and CAR T cell therapy. Furthermore, we explore the paradoxical nature of SCs, which can induce growth arrest in adjacent neoplastic cells and recruit immunomodulatory cells that contribute to tumor suppression. Therefore, we utilize SCs membrane as vehicles to elicit antitumor immunity and potentially augment existing anti-cancer therapies. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of SCs detection, elimination or utilization.

Phage libraries are now amongst the most prominent approaches for the identification of high-affinity antibodies/peptides from billions of displayed phages in a specific library through the biopanning process. Due to its ability to discover potential therapeutic candidates that bind specifically to targets, phage display has gained considerable attention in targeted therapy. Using this approach, peptides with high-affinity and specificity can be identified for potential therapeutic or diagnostic use. Furthermore, phage libraries can be used to rapidly screen and identify novel antibodies to develop immunotherapeutics. The Food and Drug Administration (FDA) has approved several phage display-derived peptides and antibodies for the treatment of different diseases. In the current review, we provided a comprehensive insight into the role of phage display-derived peptides and antibodies in the treatment of different diseases including cancers, infectious diseases and neurological disorders. We also explored the applications of phage display in targeted drug delivery, gene therapy, and CAR T-cell.

T Cell Engager (TCE)s are an exciting therapeutic modality in immuno-oncology that acts to bypass antigen presentation and forms a direct link between cancer and immune cells in the Tumor Microenvironment (TME). TCEs are efficacious only when the drug is bound to both immune and cancer cell targets. Therefore, approaches that maximize the formation of the drug-target trimer in the TME are expected to increase the drug's efficacy. In this study, we quantitatively investigate how the concentration of ternary complex and its biodistribution depend on both the targets' specific properties and the design characteristics of the TCE, and specifically on the binding kinetics of the drug to its targets. A simplified mathematical model of drug-target interactions is considered here, with insights from the "three-body" problem applied to the model. Parameter identifiability analysis performed on the model demonstrates that steady state data, which is often available at the early pre-clinical stages, is sufficient to estimate the binding affinity of the TCE molecule to both targets. We used the model to analyze several existing antibodies, both clinically approved and under development, to explore their common kinetic features. The manuscript concludes with an assessment of a full quantitative pharmacology model that accounts for drug disposition into the peripheral compartment.

Immunotherapy has been recognized as a significant advancement in cancer treatment by promoting the body's immune system to identify and eliminate cancer cells more effectively. Unlike conventional therapies, immunotherapy can enhance the natural capabilities of human immune system. Chimeric Antigen Receptor T-cell (CAR-T) therapy involves genetical-modified T-cells from patients to better catch and attack cancer cells. Up to date, CAR-T therapy has shown particular promise in treating certain types of leukemia and lymphoma, highlighting the transformative potential of immunotherapy.

Literature data search using PubMed, CNKI, and Wanfang were searched to collect eligible studies up to January 2025. The primary outcomes of complete response rate (CRR), objective response rate (ORR), dead rate (DR), and other adverse reactions were evaluated. Secondary outcomes (CRR, ORR, and DR) of subgroup analysis from different cancer types, origins, and outcomes for survival rate were analyzed for our final results. A total of 649 studies were initially identified through database searching. After removing duplicates and non-clinical cancer studies, 32 eligible studies were included in this work. The pooled data included 819 patients for objective response rate (ORR), 843 patients for complete response rate (CRR), and 868 patients for dead event. In the included studies, 24 reported ORR data, revealing an objective response rate of 84.86% (695/819) with little heterogeneity (OR: 0.87, 95% CI 0.80-0.91, P = < 0.01, I2 = 61%); 24 studies showed a CRR of 65.30% (491/843) with significant heterogeneity (OR: 0.58, 95% CI: 0.43-0.72, P < 0.01, I2 = 84%); 27 studies showed a mortality rate of 23.73% (206/868) with significant heterogeneity (OR: 0.19, 95% CI: 0.11-0.32, P < 0.01, I2 = 77%). Subgroup analysis based on cancer type revealed that ORR was higher in multiple myeloma (86.77%, 400/461) compared with leukemia (84.92%, 259/305) and lymphoma (67.92%, 36/53). In parallel, heterogeneity observed based on case origins suggested that Chinese cases showed significantly higher ORR, CRR, and survival rates compared with American ones.

This meta-analysis provides valuable insights into the potential of immunotherapy, particularly CAR-T, in cancer treatment. Findings showed the different efficacy and safety of immunotherapy in treating multiple cancers, with various objective response rates. Continued studies from more trials with different populations are needed to optimize their efficacy in further cancer treatment and precision medicine.

Acute myeloid leukemia (AML) exhibits a pronounced ability to develop drug resistance and undergo disease relapse. Recent research has noticed that resistance to treatments could substantially be attributed to drug-tolerant persister (DTP) cells, which are capable of surviving under therapeutic pressures. These are transient, reversibly dormant cells with the capability to act as a reservoir for disease relapse. DTP cells utilize diverse adaptive strategies to optimize the ecological niche, undergo metabolic reprogramming, and interact with microenvironment. The persister state of AML is established through transient cellular reprogramming, thus allowing cells to survive the initial phase of drug therapy and develop drug resistance. Our review explores the identification and phenotypic characteristics of AML DTP cells, as well as their clinical relevance. We summarize the mechanisms underlying the persistence of AML DTP cells and the molecular attributes that define the DTP state. We further address the current challenges and future prospects of DTP-targeting approaches. Understanding these features may provide critical insights into novel therapeutic strategies aimed at targeting AML DTP cells, especially in the new era of immunotherapy against AML.

Chimeric antigen receptor (CAR)-T cell immunotherapy, effective in blood cancers, shows limited success in solid tumors, such as prostate, pancreatic, and brain cancers due, in part, to an immunosuppressive tumor microenvironment (TME). Immunosuppression affects various cell types, including tumor cells, macrophages, and endothelial cells. Conventional murine-based models offer limited concordance with human immunology and cancer biology. Therefore, we have developed a human "tumor-on-a-chip" (TOC) platform to model elements of immunosuppression at high spatiotemporal resolution. Our TOC features an endothelial cell-lined channel that mimics features of an in vivo capillary, such as cell attachment and extravasation across the endothelium and into the TME. Using 70 kDa dextran and fluorescence-recovery-after-photobleaching (FRAP), we confirmed physiologic interstitial flow velocities (0.1-1 μm s-1). Our device demonstrates that tumor-derived factors can diffuse in the opposite direction of interstitial flow to reach the endothelium up to 200 μm away, and at concentrations as high as 20% of those at the tumor margin. M2-like immunosuppressive macrophages and endothelial cells affect prostate tumor cell growth, clustering, and migration. M2-like macrophages also induce PD-L1 and inhibit ICAM-1 gene expression on the adjacent endothelium in a pattern that limits CAR-T cell extravasation and effector function. This observation is abrogated in the presence of the anti-PD-L1 drug atezolizumab. These results provide mechanistic insight for in vivo observations showing limited CAR-T cell extravasation and effector function in solid tumors. Furthermore, they point to a specific role of M2 macrophages in driving CAR-T cell migration into and within the TME and could prove useful in the development of novel therapies to improve solid tumor CAR-T cell therapies.

Bladder cancer, as a highly heterogeneous malignant tumor of the urinary system, is significantly affected by tumor metabolic reprogramming in its response to immunotherapy. This review systematically elaborates on the molecular mechanisms of abnormal glucose and lipid metabolism in the bladder cancer microenvironment and immune escape, and discusses precision treatment strategies based on metabolic regulation. In the future, it will be necessary to combine spatiotemporal omics and artificial intelligence technologies to construct a multi-target intervention system for the metabolic-immune interaction network, promoting a paradigm shift in precision treatment for bladder cancer.

Compared with other metastatic sites, breast cancer brain metastases (BCBMs) are associated with the shortest survival time. In addition, human epidermal growth factor receptor 2 (HER2) is observed to be amplified in 20-25% of breast cancer cases where it is a poor prognostic factor for brain metastases. Various anti-HER2 targeted therapies have brought both new opportunities and challenges to patients with HER2-positive BCBM over the past decade. However, prolonging survival time and improving quality of life of patients have become controversial issues in the field of clinical research on BCBMs. On the basis of the latest literature, the present review documents the anti-HER2 targeted drugs applied in patients with HER2-positive BCBM. Further studies on the efficacy and safety of novel HER2-targeted drugs and combined or sequential therapy in clinical treatment are expected to provide more effective strategies for the treatment of patients with HER2-positive BCBM.

Despite current technological advancements in the treatment of glioma, immediate alleviation of symptoms can be catered by therapeutic modalities, including surgery, chemotherapy, and combinatorial radiotherapy that exploit aberrations of glioma. Additionally, a small number of target antigens, their heterogeneity, and immune evasion are the potential reasons for developing targeted therapies. This oncologic milestone has catalyzed interest in developing immunotherapies against Glioblastoma to improve overall survival and cure patients with high-grade glioma. The next-gen CAR-T Cell therapy is one of the effective immunotherapeutic strategies in which autologous T cells have been modified to express receptors against GBM and it modulates cytotoxicity.

In this review article, we examine preclinical and clinical outcomes, and limitations as well as present cutting-edge techniques to improve the function of CAR-T cell therapy and explore the possibility of combination therapy.

To date, several CAR T-cell therapies are being evaluated in clinical trials for GBM and other brain malignancies and multiple preclinical studies have demonstrated encouraging outcomes.

CAR-T cell therapy represents a promising therapeutic paradigm in the treatment of solid tumors but a few limitations include, the blood-brain barrier (BBB), antigen escape, tumor microenvironment (TME), tumor heterogeneity, and its plasticity that suppresses immune responses weakens the ability of this therapy. Additional investigation is required that can accurately identify the targets and reflect the similar architecture of glioblastoma, thus optimizing the efficiency of CAR-T cell therapy; allowing for the selection of patients most likely to benefit from immuno-based treatments.

Marred by a median survival of only around 12-15 months coupled with poor prognosis and effective therapeutic deprived drug armory, treatment/management of glioblastoma has proved to be a daunting task. Surgical resection, flanked by radiotherapy and chemotherapy with temozolomide, stands as the standard of care; however, this trimodal therapy often manifests limited efficacy due to the heterogeneous and highly infiltrative nature of GBM cells. In addition, the existence of the blood-brain barrier, tumor microenvironment, and the immunosuppressive nature of GBM, along with the encountered resistance of GBM cells towards conventional therapy, also hinders the therapeutic applications of chemotherapeutics in GBM. This review presents key insights into the molecular pathology of GBM, including genetic mutations, signaling pathways, and tumor microenvironment characteristics. Recent innovations such as immunotherapy, oncolytic viral therapies, vaccines, nanotechnology, electric field, and cancer neuroscience, as well as their clinical progress, have been covered. In addition, this compilation also encompasses a discussion on the role of personalized medicine in tailoring treatments based on individual tumor profiles, an approach that is gradually shifting the paradigm in GBM management. Endowed with the learnings imbibed from past failures coupled with the zeal to embrace novel/multidisciplinary approaches, researchers appear to be on the right track to pinpoint more effective and durable solutions in the context of GBM treatment.

The Ubiquitin A (UBA) protein family contains seven members that protect themselves or their interacting proteins from proteasome degradation. The UBA protein family regulates cell proliferation, cell cycle, invasion, migration, apoptosis, autophagy, tissue differentiation, and immune response. With the deepening of research, the UBA protein family has been found to be abnormally expressed in a variety of tumor diseases, and the clarification of its relationship with tumor diseases can be used as a molecular therapeutic target and have an important role in the prognosis of tumors. In this paper, we review the structure, biological process, target therapy, and biomarkers of the UBA protein family to provide new ideas for the diagnosis and treatment of tumors.

Immunotherapy targeting tumor antigens and immune checkpoint inhibitors has garnered significant attention in cancer treatment. Synthetic gene circuits are developed, encoded in plasmids, which regulate the expression of tumor antigens shared with embryonic stem cells (ESCs) and PD-L1 nanobody (PD-L1 nb) in response to bezafibrate stimulation. This approach significantly minimizes side effects and improved therapeutic efficacy. The transcriptional switches leverage the interaction between the bezafibrate-responsive transcriptional activator PPARγ and RXRα, which are fused with the VPR/VP64/p65 activation domains (AD) and the Gal4 DNA-binding domain (DBD), respectively. These synthetic constructs are validated and their ability to modulate gene expression upon bezafibrate treatment are confirmed. Notably, the gene expression is precise and tunable in response to bezafibrate administration. HEK293T cells or ESCs are employed to deliver this gene circuit, or the plasmids containing the circuit into the tumor are directly injected. Administration of bezafibrate reduces tumor growth, increases specific CD8+ T cells, and mitigates CD8+ T cell exhaustion, underscoring the feasibility and effectiveness of the approach. ESC-based and intratumoral delivery of the synthetic gene circuits and cargo genes, particularly PD-L1 nb, significantly inhibit tumor growth. PD-L1 nb effectively blocks PD-L1 expression both in vitro and in vivo, as confirmed by using a mutant PD-L1 nb sequence.

Cytokine storm (CS) is a severe systemic inflammatory syndrome characterized by the excessive activation of immune cells and a significant increase in circulating levels of cytokines. This pathological process is implicated in the development of life-threatening conditions such as fulminant myocarditis (FM), acute respiratory distress syndrome (ARDS), primary or secondary hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome (CRS) associated with chimeric antigen receptor-modified T (CAR-T) therapy, and grade III to IV acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. The significant involvement of the JAK-STAT pathway, Toll-like receptors, neutrophil extracellular traps, NLRP3 inflammasome, and other signaling pathways has been recognized in the pathogenesis of CS. Therapies targeting these pathways have been developed or are currently being investigated. While novel drugs have demonstrated promising therapeutic efficacy in mitigating CS, the overall mortality rate of CS resulting from underlying diseases remains high. In the clinical setting, the management of CS typically necessitates a multidisciplinary team strategy encompassing the removal of abnormal inflammatory or immune system activation, the preservation of vital organ function, the treatment of the underlying disease, and the provision of life supportive therapy. This review provides a comprehensive overview of the key signaling pathways and associated cytokines implicated in CS, elucidates the impact of dysregulated immune cell activation, and delineates the resultant organ injury associated with CS. In addition, we offer insights and current literature on the management of CS in cases of FM, ARDS, systemic inflammatory response syndrome, treatment-induced CRS, HLH, and other related conditions.

Hepatocellular carcinoma stands as one of the foremost contributors to cancer-associated fatalities globally, and the limitations of traditional treatment methods have prompted researchers to explore new therapeutic options. Recently, cell therapy has emerged as a promising approach for HCC, showing significant potential in improving patient outcomes. This review article explores the use of cell therapy for HCC, covering different types, the mechanisms behind their effectiveness, recent advancements in clinical trials, and ongoing challenges. This article aims to provide insightful perspectives for future research and clinical applications in treating HCC by synthesizing current knowledge.

Pancreatic cancer is a deadly disease with a low survival rate, particularly in its advanced stages. Advanced pancreatic cancer remains a major clinical challenge due to limited treatment options. Surgical resection may not always be feasible, and traditional chemotherapy often shows restricted effectiveness. As a result, researchers are exploring a multifaceted therapeutic approach targeting the genetic and molecular drivers of the disease. A combination of molecular profiling and targeted therapies are being investigated to improve outcomes and address the shortcomings of traditional treatments. The focus of this review is to provide a summary of current and completed clinical trials for the treatment of advanced pancreatic cancer. This includes adagrasib (a KRAS inhibitor), olaparib (a PARP inhibitor for BRCA mutations), APG-1387 (an IAP antagonist), minnelide (an anti-stromal agent), arimastat (an MMP inhibitor), MK-0646 (an IGF1R inhibitor), sirolimus (an mTOR inhibitor), and metabolic inhibitors. These agents are being evaluated both as standalone treatments and in combination with standard therapy. Furthermore, we have summarized novel approaches such as cancer vaccines and ablation techniques as emerging strategies in the treatment of advanced pancreatic cancer. We have also examined the challenges in treating advanced pancreatic cancer and the factors contributing to therapeutic failure, which may offer valuable insights for developing more effective treatment strategies and innovative drug designs.

Immunotherapy employing natural killer (NK) cells has emerged as a transformative approach to treating hematological malignancies. The reprogramming of NK cells by incorporating a chimeric antigen receptor (CAR) equipped with potent signaling domains has demonstrated efficacy in enhancing NK cell responses and improving specificity in recognizing cancerous cells. Despite these advancements, the primary challenge in implementing allogeneic NK cell therapy requiring a viable donor source for clinically relevant doses remains unresolved. This study tested NK cells obtained from leukoreduction filters (LRF) post-blood donation to address the need for an efficient and scalable supply of NK cells for generating anti-BCMA CAR NK cells. LRF-NK cells were isolated under sterile conditions and compared with peripheral blood (PB)-derived NK cells in terms of immunophenotype, proliferation capacity, and functional characteristics. Notably, no significant differences in inherent characteristics were observed between LRF-NK and PB-NK cells. Subsequently, both NK cell populations were employed to generate anti-BCMA CAR-NK cells. The data revealed a high specific cytotoxicity of Anti-BCMA CAR LRF-NK cells during co-culture with U266-B1 cells (70.3 ± 4.78%), surpassing that observed with CCRF-CEM cells (31.3 ± 2.35%) and similar to Anti-BCMA CAR PB-NK cells. Furthermore, the expression of IFN-γ and Granzyme B, following the co-culture of Anti-BCMA CAR LRF-NK cells with target cells, mirrored that observed in Anti-BCMA CAR PB-NK cells. This study provides the rationale and feasibility of utilizing LRF-NK cells as a safe, high-yield, accessible, and optimal cost-effective source for cancer immunotherapy.

Malignant pleural effusion (MPE) remains a clinical issue since it is associated with advanced-stage cancers and dismal survival, with immunosuppressive tumor microenvironment (TME) and ineffective drug delivery. Conventional therapies such as thoracentesis and pleurodesis are for symptom relief but palliative, without inducing immunity and prolonging survival. Emerging new bioengineered drugs, synergizing with immunotherapies, offer a new paradigm by dual-targeting TME remodeling and immune activation. These technologies leverage nanotechnology, gene editing, and biomaterials to offer precise spatiotemporal control. This review illustrates the molecular mechanism of the immunosuppressive TME in MPE. It examines the newest bioengineering platforms-such as cytokine-encapsulated nanoparticles and oncolytic viruses-that can reactivate immune mechanisms. We highlight preclinical and clinical evidence of the effectiveness of combinatorial strategies in overcoming local immune tolerance and potential risks in adverse events. While the clinical transformation challenge remains, future directions necessitate cross-disciplinary convergence to engineer intelligent delivery vehicles and predictive biomarkers for patient stratification. By integrating immunotherapy with bioengineering, this strategy not only restores antitumor immunity but also portends a new epoch of precision medicine for MPE.

Idiopathic pulmonary fibrosis (IPF) is a lethal disease with an unknown etiology and complex pathophysiology that are not fully understood. The disease involves intricate cellular interplay, particularly among various immune cells. Currently, there is no treatment capable of reversing the fibrotic process or aiding lung regeneration. Hepatocyte growth factor (HGF) has demonstrated antifibrotic properties, whereas the adoptive transfer of modified T cells is a well-established treatment for various malignancies. We aimed to understand the dynamics of T cells in the progression of lung fibrosis and to study the therapeutic benefit of adoptive T cell transfer in a bleomycin-injured mouse lung (BLM) model.

T cells were isolated from the spleen of naïve mice and transfected in vitro with mouse HGF plasmid and were administered intratracheally to the mice lungs 7 days post-bleomycin injury to the lung. Lung tissue and bronchoalveolar lavage were collected and analyzed using flow cytometry, histology, qRT-PCR, ELISA, and hydroxyproline assay.

Our findings demonstrate the successful T cell therapy of bleomycin-induced lung injury through the adoptive transfer of HGF-transfected T cells in mice. This treatment resulted in decreased collagen deposition and a balancing of immune cell exhaustion and cytokine homeostasis compared with untreated controls. In vitro testing showed enhanced apoptosis in myofibroblasts induced by HGF-overexpressing T cells.

Taken together, our data highlight the great potential of adoptive T cell transfer as an emerging therapy to counteract lung fibrosis.

Small cell lung cancer (SCLC) is an aggressive tumor characterized by early metastasis and resistance to treatment, making it a prime target for therapeutic investigation. The current standard of care for frontline treatment involves a combination of chemotherapeutic agents and immune checkpoint inhibitors (ICIs), though durability of response remains limited. The genetic heterogeneity of SCLC also complicates the development of new therapeutic options. Adoptive cell therapies show promise by targeting specific mutations in order to increase efficacy and minimize toxicity. There has been significant investigation in three therapeutic classes for application towards SCLC: antibody drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR)-T cell therapies. This review summarizes the recent advances and challenges in the development of adoptive cell therapies. Genetic targets such as delta-like ligand 3 (DLL3), trophoblast cell surface antigen 2 (Trop2), B7-H3 (CD276), gangliosides disialoganglioside GD2 (GD2) and ganglioside GM2 (GM2) have been found to be expressed in SCLC, which makes them prime targets for therapy development. While investigated therapies such as rovalpituzumab tesirine (Rova-T) have failed, several insights from these trials have led to the development of compelling new agents such as sacituzumab govitecan (SG), ifinatamab deruxtecan (I-DXd), tarlatamab, and DLL3-targeted CAR-T cells. Advancing development of molecular testing and improving targeted approaches remain integral to pushing forward the progress of adoptive cell therapies in SCLC.

Immunotherapy has emerged as a preeminent force in the domain of cancer therapeutics and achieved remarkable breakthroughs. Nevertheless, the high resistance has become the most substantial impediment restricting its clinical efficacy. Beta-2 microglobulin (B2M), the light chain of major histocompatibility complex (MHC) class I, plays an indispensable part by presenting tumor antigens to cytotoxic T lymphocytes (CTLs) for exerting anti-tumor effects. Accumulating evidence indicates that B2M mutation/defect is one of the key mechanisms underlying tumor immunotherapy resistance. Therefore, elucidating the role played by B2M and devising effective strategies to battle against resistance are pressing issues. This review will systematically expound upon them, aiming to provide insight into the potential of B2M as a promising target in anticancer immune response.

IGV-001 is a type of cellular immunotherapy currently being investigated for treating glioblastoma (NCT04485949). It uses the patient's tumor to elicit an autologous immune response.

The process involves (i) craniotomy for maximum safe resection of the glioblastoma, (ii) ex-vivo treatment of the tumor with an anti-sense oligodeoxynucleotide against insulin-like growth factor 1 receptor followed by irradiation, (iii) placement of the treated tumor in multiple bio-diffusion chambers, which are implanted into the patient's abdominal sheath to elicit an immune response, and (iv) explantation of the chambers 48 hours later. The clinical trial was open at 32 sites in the United States, and eligible subjects were randomized in a 2:1 ratio to receive bio-diffusion chambers containing either conditioned glioblastoma tissue or a placebo. Patients subsequently proceeded to standard-of-care treatment with concomitant radiation-temozolomide, followed by 6 cycles of adjuvant temozolomide.

The execution of the IGV-001 protocol procedure is complicated and involves a multi-step process requiring mobilization of multiple services within the cancer center of a tertiary care hospital, including neurosurgery, neuro-oncology, radiation oncology, neuroradiology, cancer clinical trial office, and operating room personnel to fulfill the pre-specified protocol requirements in a timely fashion.

We have learned a great deal in the process of developing and executing our internal procedures for this clinical trial. Our description of the IGV-001 protocol workflow may serve as a "blueprint" for future implementation of this type of cellular immunotherapy at other centers. We further discuss some of the lessons we have learned during the trial.

Thyroid cancer generally boasts a favorable prognosis; however, advanced and refractory cases exhibit aggressive characteristics and resistance to conventional therapies, necessitating the investigation of innovative treatment modalities. Immunotherapy, which harnesses the body's immune system to target cancer cells, has shown considerable promise for specific thyroid cancer subtypes.

This review article aims to encapsulate the latest advancements in immunotherapy for thyroid cancer, examining its mechanisms, therapeutic efficacy, ongoing challenges, and the potential benefits of combination therapy approaches.

An extensive literature review and critical analysis of clinical trial data were conducted to inform this synthesis.

The review reveals that immunotherapy strategies, encompassing immune checkpoint inhibitors, CAR-T cell therapy, tumor vaccines, and immunomodulators, are demonstrating efficacy in the treatment of thyroid cancer. Notably, checkpoint inhibitors have been particularly effective in anaplastic and poorly differentiated thyroid cancers, albeit with challenges such as treatment resistance and adverse effects. The application of CAR-T cell therapy, successful in hematologic cancers, provides a novel perspective for thyroid cancer treatment, although its efficacy in solid tumors requires further study. Additionally, research into tumor vaccines and immunomodulators is advancing, with preliminary evidence suggesting their therapeutic potential for thyroid cancer patients.

The recognition of the immune microenvironment's role in treatment responsiveness is pivotal for enhancing the care of thyroid cancer patients. This review underscores the significance of combination therapy as a means to optimize treatment outcomes and charts a course for future research endeavors to broaden the spectrum of effective treatment options available to thyroid cancer patients.

Over the past several years, the therapeutic landscape for patients with advanced, unresectable, or metastatic hepatocellular carcinoma has been transformed by the incorporation of checkpoint inhibitor immunotherapy into the treatment paradigm. Frontline systemic treatment options have expanded beyond anti-angiogenic tyrosine kinase inhibitors, such as sorafenib, to a combination of immunotherapy approaches, including atezolizumab plus bevacizumab and durvalumab plus tremelimumab, both of which have demonstrated superior response and survival to sorafenib. Additionally, combination treatments with checkpoint inhibitors and tyrosine kinase inhibitors have been investigated with variable success. In this review, we discuss these advances in systemic treatment with immunotherapy, with a focus on understanding both the underlying biology and mechanism of these strategies and their efficacy outcomes in clinical trials. We also review challenges in identifying predictive biomarkers of treatments and discuss future directions with novel immunotherapy targets.

Metastatic castration-resistant prostate cancer (mCRPC) is driven by a complex network of resistance mechanisms against standard-of-care therapies, resulting in poor long-term outcomes. This review offers a uniquely comprehensive and integrative perspective on these resistance pathways, systematically examining both androgen receptor (AR)-dependent factors (including AR overexpression, point mutations, glucocorticoid receptor signaling, splice variants, post-translational modifications, altered coregulators, and intratumoral hormone biosynthesis) and AR-independent pathways (such as neuroendocrine differentiation, lineage plasticity, and alternative growth factor signaling). We also highlight resistance mechanisms influencing immunotherapy, chemotherapy, radiopharmaceutical therapy and targeted therapy. By synthesizing emerging insights across these domains, this review not only clarifies the underlying biology of mCRPC resistance but also identifies key leverage points for more effective interventions. Building on this foundation, we propose a forward-looking framework for overcoming mCRPC drug resistance, emphasizing the importance of biomarker-guided patient selection, combination strategies that simultaneously target multiple resistance mechanisms, and novel therapies under investigation. These recommendations are intended to guide future clinical trial designs and research priorities that move beyond incremental improvements. Ultimately, this comprehensive synthesis aims to serve as a resource for clinicians and researchers to accelerate the development of durable, precision-based treatment strategies in mCRPC.

Melanoma, an aggressive skin cancer, presents significant therapeutic challenges. Consequently, innovative treatment strategies beyond conventional chemotherapy, radiation, and surgery are actively explored. This review discusses the evolution of immunotherapy in advanced melanoma, highlighting PD-1/PD-L1 inhibitors, mRNA vaccines, Talimogene Laherparepvec (T-VEC), and tumor-infiltrating lymphocyte (TIL) therapies. PD-1/PD-L1 inhibitors such as pembrolizumab and nivolumab block immune checkpoints, promoting T-cell cytotoxic activity and improving overall survival in patients with advanced melanoma. T-VEC, a modified oncolytic herpes virus, promotes a systemic anti-tumor response while simultaneously lysing malignant cells. mRNA vaccines, such as Moderna's mRNA-4157/V940, take advantage of malignant-cell-specific neoantigens to amplify the adaptive immune response while protecting healthy tissue. TIL therapy is a form of therapy involving ex vivo expansion and reinfusion of the patient's tumor-specific lymphocytes and has been shown to provide durable tumor control. While these therapies have demonstrated promising clinical outcomes, challenges such as tumor resistance, high financial burden, and limited accessibility pose challenges to their widespread use. This review explores combination therapies such as PD-L1 inhibitors with mRNA vaccines, or TIL therapy, which aim to enhance treatment through synergistic approaches. Further research is required to optimize these combinations, address barriers preventing their use, and control adverse events.

As a novel immunotherapy, chimeric antigen receptor T (CAR-T) cell technology is successful in treating hematologic malignancies, and exhibits potential benefits in partial solid tumors. Therapies targeting one antigen have some weaknesses, and dual-targeted CAR-T cells may be a better option. Alpha-fetoprotein (AFP) and glypican-3 (GPC3) are both highly expressed in hepatocellular carcinoma (HCC) and serve as important markers. Our study aimed to compare the cytotoxicity effect of AFP and GPC3 dual-targeted CAR-T cells on HCC cells in vitro and its therapeutic effects on a SCID xenograft model with those of single-targeted CAR-T cells.

pLVX lentivirus vectors loaded with AFP CAR, GPC3 CAR, or AFP-GPC3 CAR constructs were transfected into human T lymphocytes. Control T, AFP CAR-T, GPC3 CAR-T, and AFP-GPC3 CAR-T cells were used as effector cells, and HLE (AFP-GPC3-), Sh-GPC3-Huh-7 (AFP+), Sh-AFP-Huh-7 (GPC3+), and Huh-7 (AFP+GPC3+) cells were used as target cells. After their co-culture for 6 h, the LDH cytotoxicity assay was employed to estimate the cell-killing effects of CAR-T cells on the target HCC cells. SCID mice bearing Huh-7 cell-derived neoplasms were injected with CAR-T cells, after which the pathological changes, CD3ζ expression, and IL-2 and IFN-γ levels in mouse tumor tissues were determined.

AFP and GPC3 were highly expressed in Huh-7 cells. AFP-GPC3 CAR-T cells exerted significant cell-killing effects on the HCC cells that expressed specific targeting antigen molecules (AFP and GPC3). Besides, AFP-GPC3 CAR-T cells better promoted Th cytokine secretion by Huh-7 cells than AFP CAR-T and GPC3 CAR-T cells. In vivo results suggested that AFP-GPC3 CAR-T cells better inhibited the growth of Huh-7 cell (AFP+GPC3+)-derived neoplasms than AFP CAR-T and GPC3 CAR-T cells.

AFP and GPC3 dual-targeted CAR-T cells showed better anti-tumor effects in HCC than AFP or GPC3 single-targeted CAR-T cells.

The advent of immune-based combinations, primarily leveraging immune checkpoint inhibitors, has revolutionized the therapeutic landscape of hepatocellular carcinoma (HCC). The current scenario features multiple therapies that have shown superiority over tyrosine kinase inhibitors; however, the absence of direct comparisons and validated prognostic biomarkers complicates therapeutic decision-making. Additionally, a significant proportion of patients still exhibit primary or secondary resistance to existing immunotherapies, underscoring the ongoing need for novel therapeutic strategies.

This narrative review discusses current strategies aimed at improving the efficacy of immunotherapy for HCC, focusing on the following aspects: available therapeutic options, identification of prognostic biomarkers, approaches to overcoming resistance (including the development of neoantigen vaccines), and the exploration of adjuvant and neoadjuvant strategies.

The future of systemic therapies for HCC is likely to be driven by advancements in immunotherapy. Key areas of exploration for the coming years include the discovery of novel checkpoint inhibitors or complementary agents to enhance tumor response when combined with existing treatments, a shift toward neoadjuvant/perioperative trials instead of traditional adjuvant approaches, and the development of personalized neoantigen vaccines.

The development of an effective HIV-1 vaccine remains a formidable challenge in biomedical research. Despite significant advancements in our understanding of HIV biology and pathogenesis, progress has been impeded by factors such as the virus's genetic diversity, high mutation rates, and its ability to establish latent reservoirs. Recent innovative approaches, including mosaic vaccines and mRNA technology to induce broadly neutralizing antibodies, have shown promise. However, the efficacy of these vaccines has been modest, with the best results achieving approximately 30% effectiveness. Ongoing research emphasizes the necessity of a multifaceted strategy to overcome these obstacles and achieve a breakthrough in HIV-1 vaccine development. This review summarizes current approaches utilized to further understand HIV-1 biology and to create a global vaccine. We discuss the impact of these approaches on vaccine development for other diseases, including COVID-19, influenza, and Zika virus. Additionally, we highlight the specific limitations faced with each approach and present the methods researchers employ to overcome these challenges. These innovative techniques, which have demonstrated preclinical and clinical success, have advanced the field closer to the ultimate goal of developing a global HIV-1 vaccine. Leveraging these advancements will enable significant strides in combating HIV-1 and other infectious diseases, ultimately improving global health outcomes.

Cutaneous melanoma is one of the most aggressive skin cancers originating from skin pigment cells. Patients with advanced melanoma suffer a poor prognosis and generally cannot benefit well from surgical resection and chemo/target therapy due to metastasis and drug resistance. Thus, adoptive cell therapy (ACT), employing immune cells with specific tumor-recognizing receptors, has emerged as a promising therapeutic approach to display on-tumor toxicity. This review discusses the application, efficacy, limitations, as well as future prospects of four commonly utilized approaches -including tumor-infiltrating lymphocytes, chimeric antigen receptor (CAR) T cell, engineered T-cell receptor T cells, and chimeric antigen receptor NK cells- in the context of malignant melanoma.

Objectives:Neurotoxicity, encephalopathy, and seizures can occur following chimeric antigen receptor (CAR)-T cell therapy. Our aim was to assess what value electroencephalography (EEG) offers for people undergoing CAR-T treatment in clinical practice, including possible diagnostic, management, and prognostic roles. Methods: All patients developing CAR-T related neurotoxicity referred for EEG were eligible for inclusion. Reasons for EEG referral and qualitative EEG findings were analysed and reported. The relationship between objective quantitative EEG (QEEG) encephalopathy grade and clinical neurotoxicity (immune effector cell-associated neurotoxicity syndrome; ICANS) grade was determined. The prognostic ability of QEEG grade was assessed for survival and functional status. Results: Twenty-eight patients with 53 EEG recordings were included. Common reasons given on EEG referrals were possible seizure diagnosis (n = 38), reduced consciousness (n = 8), and superimposed cerebral infection (n = 4). Four focal seizures were detected on three (3/53; 5.7%) EEGs. There was a moderately positive correlation between QEEG grade and ICANS grade (r = + 0.41, p = .030). QEEG grade could not predict survival at 3 months (Area Under Curve; AUC = 0.673) or 6 months (AUC = 0.578), nor could it predict functional status at 1 month (r = + 0.40; p = .080), 3 months (r = + 0.19; p = .439), or time to return to baseline (r = + 0.32; p = .156). Conclusions: EEG was useful in seizure diagnosis. QEEG has a possible role as a specific biomarker of encephalopathy/neurotoxicity. EEG generated no tangible changes in patient management. QEEG was unable to prognosticate survival or functional status.

Breast cancer will overtake all other cancers in terms of diagnoses in 2024. Breast cancer counts highest among women in terms of cancer incidence and death rates. Innovative treatment approaches are desperately needed because treatment resistance brought on by current clinical drugs impedes therapeutic efficacy. The T cell-based immunotherapy known as chimeric antigen receptor (CAR) T cell treatment, which uses the patient's immune cells to fight cancer, has demonstrated remarkable efficacy in treating hematologic malignancies; nevertheless, the treatment effects in solid tumors, like breast cancer, have not lived up to expectations. We discuss in detail the role of tumor-associated antigens in breast cancer, current clinical trials, barriers to the intended therapeutic effects of CAR-T cell therapy, and potential ways to increase treatment efficacy. Finally, our review aims to stimulate readers' curiosity by summarizing the most recent advancements in CAR-T cell therapy for breast cancer.

To date, genetically modified organoids are emerging as a promising 3D modeling tool aimed at solving genetically relevant clinical and biomedical problems for regenerative medicine and tissue engineering. As an optimal vehicle for gene delivery, genetically modified organoids can enhance or reduce the expression of target genes through virus and non-virus-based gene transfection methods to achieve tissue regeneration. Animal experiments and preclinical studies have demonstrated the beneficial role of genetically modified organoids in various aspects of organ regeneration, including thymus, lacrimal glands, brain, lung, kidney, photoreceptors, etc. Furthermore, the technology offers a potential treatment option for various diseases, such as Fabry disease, non-alcoholic steatohepatitis, and Lynch syndrome. Nevertheless, the uncertain safety of genetic modification, the risk of organoid application, and bionics of current genetically modified organoids are still challenging. This review summarizes the researches on genetically modified organoids in recent years, and describes the transfection methods and functions of genetically modified organoids, then introduced their applications at length. Also, the limitations and future development directions of genetically modified organoids are included.

Chimeric antigen receptor (CAR) T cell therapies have transformed outcomes for many patients with hematological malignancies. However, some patients do not respond to CAR T cell treatment, and adapting CAR T cells for treatment of solid and brain tumors has been met with many challenges, including a hostile tumor microenvironment and poor CAR T cell persistence. Thus, it is unlikely that CAR T cell therapy alone will be sufficient for consistent, complete tumor clearance across patients with cancer. Combinatorial therapies of CAR T cells and chemotherapeutics are a promising approach for overcoming this because chemotherapeutics could augment CAR T cells for improved antitumor activity or work in tandem with CAR T cells to clear tumors. Herein, we review efforts toward achieving successful CAR T cell and chemical drug combination therapies. We focus on combination therapies with approved chemotherapeutics because these will be more easily translated to the clinic but also review nonapproved chemotherapeutics and drug screens designed to reveal promising new CAR T cell and chemical drug combinations. Overall, this review highlights the promise of CAR T cell and chemotherapy combinations with a specific focus on how combinatorial therapy overcomes challenges faced by either monotherapy and supports the potential of this therapeutic strategy to improve outcomes for patients with cancer. SIGNIFICANCE STATEMENT: Improving currently available CAR T cell products via combinatorial therapy with chemotherapeutics has the potential to drastically expand the types of cancers and number of patients that could benefit from these therapies when neither alone has been sufficient to achieve tumor clearance. Herein, we provide a thorough review of the current efforts toward studying CAR T and chemotherapy combinatorial therapies and offer perspectives on optimal ways to identify new and effective combinations moving forward.

Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers. However, the benefit of immune-based treatments in GBM is limited because of the unique brain immune profiles, GBM cell heterogeneity, and immunosuppressive tumor microenvironment. In this review, we present a detailed overview of current immunotherapeutic strategies and discuss the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM. Furthermore, we provide an in-depth discussion regarding the strategies that can overcome immunotherapy resistance in GBM, which will likely require combination therapies.

Immunotherapy describes a class of therapies in which the immune system is manipulated for therapeutic benefit. These treatments include immune checkpoint inhibitors, adoptive cell therapy, and vaccines. For many hematological malignancies, immunotherapy has emerged as an essential treatment component. However, this success has yet to be replicated for solid tumors, which develop advanced physical and molecular mechanisms for suppressing and evading immune destruction. Nevertheless, cytokine immunotherapy presents a potential remedy to these barriers by delivering a proinflammatory immune signal to the tumor and thereby transforming it from immunologically "cold" to "hot." Interleukin-12 (IL-12), one of the most potent proinflammatory cytokines, was initially investigated for this purpose. However, initial murine and human studies in which IL-12 was administered systemically resulted in dangerous immunotoxicity associated with off-target immune activation. As a result, recent studies have employed advanced cell and molecular engineering approaches to reduce IL-12 toxicity while increasing or maintaining its efficacy such that its effective doses can be tolerated in humans. This review highlights such developments and identifies promising future directions.

Aortic valve disease (AVD) affects millions of people around the world, with no pharmacological intervention available. Widely considered a multi-faceted disease comprising both regurgitative pathogenesis, in which retrograde blood flows back through to the left ventricle, and aortic valve stenosis, which is characterized by the thickening, fibrosis, and subsequent mineralization of the aortic valve leaflets, limiting the anterograde flow through the valve, surgical intervention is still the main treatment, which incurs considerable risk to the patient.

Though originally thought of as a passive degeneration of the valve or a congenital malformation that has occurred before birth, the paradigm of AVD is shifting, and research into the inflammatory drivers of valve disease as a potential mechanism to modulate the pathobiology of this life-limiting pathology is taking center stage. Following limited success in mainstay therapeutics such as statins and mineralisation inhibitors, immunomodulatory strategies are being developed. Immune cell therapy has begun to be adopted in the cancer field, in which T cells (chimeric antigen receptor (CAR) T cells) are isolated from the patient, programmed to attack the cancer, and then re-administered to the patient. Within cardiac research, a novel T cell-based therapeutic approach has been developed to target lipid nanoparticles responsible for increasing cardiac fibrosis in a failing heart. With clonally expanded T-cell populations recently identified within the diseased valve, their unique epitope presentation may serve to identify novel targets for the treatment of valve disease.

Taken together, targeted T-cell therapy may hold promise as a therapeutic platform to target a multitude of diseases with an autoimmune aspect, and this review aims to frame this in the context of cardiovascular disease, delineating what is currently known in the field, both clinically and translationally.

In the past four decades, a plethora of genetic association studies have been carried out in cohorts of patients with rheumatoid arthritis. These studies have highlighted key aspects of disease pathogenesis and suggested causal mechanisms. In this review, we discuss major advances in our understanding of the genetic architecture of rheumatoid arthritis susceptibility, severity and treatment response and explain how genetics supports current models of disease pathogenesis and outcome. We outline future research directions, like Mendelian randomisation, and present a number of potential avenues for clinical translation, including risk and outcome prediction, patient stratification into treatment response groups and pharmacological applications.

Ischemic heart disease (IHD) is a prevalent cardiovascular condition that remains the primary cause of death due to its adverse ventricular remodelling and pathological changes in end-stage heart failure. As a complex pathologic condition, it involves intricate regulatory processes at the cellular and molecular levels. The immune system and cardiovascular system are closely interconnected, with immune cells playing a crucial role in maintaining cardiac health and influencing disease progression. Consequently, alterations in the cardiac microenvironment are influenced and controlled by various immune cells, such as macrophages, neutrophils, dendritic cells, eosinophils, and T-lymphocytes, along with the cytokines they produce. Furthermore, studies have revealed that Gata6+ pericardial cavity macrophages play a key role in regulating immune cell migration and subsequent myocardial tissue repair post IHD onset. This review outlines the role of immune cells in orchestrating inflammatory responses and facilitating myocardial repair following IHD, considering both macro and micro views. It also discusses innovative immune cell-based therapeutic strategies, offering new insights for further research on the pathophysiology of ischemic heart disease and immune cell-targeted therapy for IHD.

The rise of immunotherapy provided new approaches to cancer treatment. We aimed to describe the contribution of chimeric antigen receptor T cell immunotherapy to future prospects. We analyzed 8035 articles from the Web of Science Core Collection with CiteSpace that covered with various aspects with countries, institutions, authors, co-cited authors, journals, keywords, and references. The USA was the most prolific country, with the University of Pennsylvania being the most published institution. Among individual authors, June Carl H published the most articles, while Maude SL was the most frequently co-cited author. "Blood" emerged as the most cited journal. Keyword clustering revealed six core themes: "Expression," "Chimeric Antigen Receptor," "Tumor Microenvironment," "Blinatumomab," "Multiple Myeloma," and "Cytokine Release Syndrome." In the process of researching the timeline chart of keywords and references, "Large B-cell lymphoma" was located on the right side of the timeline. In the keyword prominence analysis, we found that the keywords "biomarkers," "pd-1," "antibody drug conjugate," "BCMA," and "chimeric antigen" had high explosive intensity in the recent past. We found that in terms of related diseases, "large B-cell lymphoma" and "cytokine release syndrome" are still difficult problems in the future. In the study of therapeutic methods, "BCMA," "PD-1," "chimeric antigen," and "antibody drug conjugate" deserve more attention from researchers in the future.