Immunotherapy with immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) patients only achieves response rates of 25%-30%, indicating the necessity of new therapies for non-responder patients. Since myeloid-related suppressive factors are associated with poor responses to ICI in a subgroup of HCC patients, modulation of these targets may improve response rates. Our aim was to characterize the expression of the efferocytosis receptor MERTK in HCC and to analyze its potential as a new therapeutic target. In HCC patients, MERTK was expressed by myeloid cells and was associated with poorer survival. In a murine HCC model with progressive myeloid cell infiltration, MERTK was detected in dendritic cells and macrophages with an activated phenotype, which overexpressed the checkpoint ligand PD-L1. Concomitant expression of PD-1 in tumor T-cells suggested the pertinence of combined PD-1/PD-L1 and MERTK blockade. In vivo experiments in mice showed that inhibition of MERTK improved the therapeutic effect promoted by anti-PD-1 or by ICI combinations currently approved for HCC. This effect was associated with enhanced tumor infiltration and superior activity of antigen presenting cells and effector lymphocytes. Our results indicate that MERTK may behave as a relevant target for immunotherapeutic combinations in those HCC patients with tumors enriched in a myeloid component.

Programmed cell death-1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors are considered effective alternatives for the primary treatment of recurrent metastatic cancers. However, they can induce various adverse events affecting multiple organ systems, potentially diminishing patients' quality of life, and even leading to treatment interruptions. Adverse events related to PD-1/PD-L1 inhibitors differ from those associated with CTLA-4 inhibitors and are more commonly observed in the treatment of solid tumors. This study aimed to address the knowledge gap regarding adverse events related to PD-1/PD-L1 inhibitors. A visual bibliometric network was constructed using VOSviewer, CiteSpace, R software, and the Web of Science Core Collection (WoSCC) to quantitatively analyze this research field. Future research directions were also explored. The USA ranked first in publication count and total citations. Over time, publication types transitioned from case reports to clinical trials. Research on for nivolumab was the most prevalent. The spectrum of cancers treated by PD-1/PD-L1 inhibitors expanded beyond melanoma and lung cancer to include renal cell carcinoma, esophageal cancer, and others. Common adverse events included pneumonitis, myasthenia gravis, and vitiligo. There was a significant increase in multi-phase clinical trials and studies related to biomarkers. This study offers valuable insights for potential collaborators and institutions, highlighting trends in the study of adverse events related to PD-1/PD-L1 inhibitors. The management of these adverse events has become more refined and standardized. Biomarker research and multi-phase clinical trials are likely to be key areas of focus in future studies.

CD8+ T cells shape the antitumor immune response. Here, we evaluated CD8+ T cells expressing different levels of PD-1, their functional status, and distribution in different tissues of luminal breast cancer (BC) patients. We characterized the exhaustion stages of CD8+ T cells in tumors, juxtatumoral tissues (JTs), and tumor-draining lymph nodes (TDLNs). Terminal exhausted CD8+ T cells (PD-1High CD8+) were predominant in tumors and nearly absent in other tissues. However, in all tissues evaluated, most CD8+ T cells exhibited a pre-exhausted phenotype (PD-1Int CD8+) or did not express PD-1. PD-1High and PD-1Int CD8+ T cells from tumors and JTs presented central and effector memory phenotypes, while in TDLNs were primarily central memory. TCR-β sequencing revealed higher clonality among CD8+ T cells from tumor than TDLNs, with tumor-enriched clones also detected in TDLNs. Analysis of scRNA-seq datasets from tumors and JTs of colorectal and non-small cell lung cancer patients, identified a CD8+ terminal exhaustion and a CD8+ pre-exhausted signatures. High expression of exhaustion-associated genes in BC tumors correlated with improved overall survival. Overall, PD-1 expression effectively distinguishes exhaustion stages in CD8+ T cells. PD-1Int cells found in tumors, JTs, and TDLNs represent a promising therapeutic target for cancer immunotherapy.

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.

Over the last decade, the increasing global prevalence of melanoma has sparked growing interest in immunotherapies, which show significant potential against this form of skin cancer. This research aims to offer a framework to guide future studies and inspire new research directions. In this study, we used the Web of Science Core Collection to collect papers on immunotherapy and melanoma published between 2014 and 2024. With Excel and visualization tools like VOSviewer, COOC 13.2, Citespace, and Bibliometrix (R-Tool of R-Studio), we analyzed the data to spot trends and new focuses in the research. Our findings indicate a substantial surge in research activity concerning immunotherapy and melanoma between 2014 and 2024. The USA and China emerged as leading contributors, engaging in extensive and close collaborative efforts with European counterparts. Furthermore, seven of the top 10 research institutions are located in the USA, with the MD Anderson Cancer Center in Texas being the most productive. In addition, the Journal of Cancer Immunotherapy is the journal with the most articles published in the field. Professor Georgina V. Long from the Melanoma Institute at the University of Sydney was one of the most productive scholars. Keyword analysis shows that immune checkpoint inhibitors, tumor microenvironment and targeted therapies are key areas of interest for the research community. This paper uses bibliometric analysis to outline research trends and key points in immunotherapy and melanoma from 2014 to 2024, which helps understand the current research and guides future research directions.

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.

We aimed to clarify the role of PD-L1 promoter methylation in bladder cancer by analyzing PD-L1 methylation and mRNA expression in FFPE samples, along with PD-L1 mRNA and protein levels in urine samples from bladder urothelial carcinoma patients. We analyzed PD-L1 promoter methylation in 43 bladder urothelial carcinoma tissue samples and 41 non-malignant bladder tissues using methylation-sensitive high-resolution melting analysis to assess two CpG islands (cg15837913, cg19724470). PD-L1 mRNA expression in tissues and urine samples, along with PD-L1 protein levels in urine, were evaluated. The bladder urothelial carcinoma group showed significantly higher methylation rates for cg19724470 and cg15837913 compared to controls (P = 0.016, P = 0.049 respectively). In the patient group, tissue PD-L1 mRNA expression was 15.22 times higher and urinary PD-L1 mRNA expression 6.56 times higher in the cg19724470 unmethylated group compared to the methylated group. Urinary PD-L1 protein concentration was twice as high in the cg19724470 unmethylated group compared to the methylated group. In the patients, tissue PD-L1 mRNA expression was 4.58 times higher and urinary PD-L1 mRNA expression 2.58 times higher in the cg15837913 unmethylated group compared to the methylated group. Moreover, the urinary PD-L1 protein concentration was 1.7 times higher in the cg15837913 unmethylated group than in the methylated group (P = 0.036). A positive correlation was observed between tissue PD-L1 mRNA and both urine PD-L1 mRNA and protein levels and between urine PD-L1 mRNA and protein levels. This study suggests that PD-L1 methylation may be a key epigenetic regulator influencing PD-L1 expression and disease pathogenesis in bladder urothelial carcinoma.

Cancer immunotherapy is an emerging anti-cancer strategy that enhances immune circulation by targeting the immune system. Among the various targets, HPK1, a member of the mammalian Ste20-like protein serine/threonine kinase family, serves as a crucial negative regulator of immune-mediated mechanisms, positioning it as a promising target for immunotherapy. Herein, based on the reported HPK1 inhibitors characterized by 2,4-diaminopyrimidine components, four series of derivatives were obtained through structural optimization methods. Compound 10c demonstrates significant inhibitory effects on HPK1 kinase, with an IC50 of 0.09 nM. Additionally, it markedly inhibits the phosphorylation of the downstream adaptor protein SLP76, with an IC50 of 33.74 nM, and effectively stimulates the secretion of the T cell activation marker IL-2, exhibiting an EC50 of 84.24 nM. These findings suggest that compound 10c holds considerable promise for applications in immunotherapy.

Breast cancer is the most common malignant tumor threatening women's health. Alteration in lipid metabolism plays an important role in the occurrence and development of many diseases, including breast cancer. The uptake, synthesis, and catabolism of lipids in breast cancer cells are significantly altered, among which the metabolism of fatty acids, cholesterols, sphingolipids, and glycolipids are most significantly changed. The growth, progression, metastasis, and drug resistance of breast cancer cells are tightly correlated with the increased uptake and biosynthesis of fatty acids and cholesterols and the up-regulation of fatty acid oxidation. Cholesterol and its metabolite 27-hydroxycholesterol promote the progression of breast cancer in a variety of ways. The alteration of lipid metabolism could promote the epithelial-mesenchymal transition of breast cancer cells and lead to changes in the tumor immune microenvironment that are conducive to the survival of cancer cells. While the accumulation of ceramide in cancer cells shows an inhibitory effect on breast cancer. This review focuses on lipid metabolism and elaborates on the research progress of the correlation between different lipid metabolism and the growth, progression, and drug resistance of breast cancer.

Safe and efficient drug delivery is as important as drug development. Biological barriers, such as cell membranes, present significant challenges in drug delivery, especially for newly developed protein-, nucleic acid-, and cell-based drugs. Ultrasound-mediated drug delivery systems offer a promising strategy to overcome these challenges. Ultrasound, a mechanical wave with energy, produces thermal effects, cavitation, acoustic radiation, and other biophysical effects. Used alone or in combination with microbubbles or sonosensitizers, it breaks biological barriers, enhances targeted drug delivery, reduces adverse reactions, controls drug release, switches on/off drug functions, and ultimately improves therapeutic efficiency. Various ultrasound-mediated drug delivery methods, including transdermal drug delivery, nebulization, targeted microbubble destruction, and sonodynamic therapy, are being actively explored for the treatment of various diseases. This review article introduces the principles, advantages, and applications of ultrasound-mediated drug delivery methods for improved therapeutic outcomes and discusses future prospects in this field.

Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. We modeled heterogeneous tumors comprised of "hot" and "cold" tumor populations (giving rise to T cell-rich and T cell-poor tumors, respectively) and introduced fluorescent labels to enable precise spatial tracking. We found the cold tumor cell population exerted a "dominant cold" effect in mixed tumors. Strikingly, spatial analysis revealed that the tumor cells themselves created distinct local microenvironments within heterogeneous tumors: regions occupied by cold tumor cells showed pronounced immunosuppression, harboring increased CD206Hi macrophages and diminished local T cell function. This inferior T cell activity in cold regions persisted even after immunotherapy and mechanistically was mediated by CX3CL1 produced by the cold tumor cells. An immune cold tumor population within a heterogeneous tumor thus impairs tumor immunity on both a tumor-wide and a highly localized spatial scale.

Immune checkpoint inhibitor (ICI) therapy is an efficacious cancer treatment, often resulting in autoimmune off-target effects. Magnetic resonance imaging (MRI) has been a recommended investigation for ICI-related hypophysitis. We sought to identify the frequency of identifiable MRI changes.

A retrospective case-control audit was performed of individuals who received one or more ICI between January 2018 and December 2023 at a single tertiary referral centre in Melbourne, Australia.

Individuals requiring hormone supplementation were screened for hypophysitis. A randomly selected control group receiving ICI demonstrated normal pituitary function at the time of MRI.

Fifty-four (6.9%) of 778 individuals who received ICI therapy were diagnosed with ICI-related hypophysitis. 43 had an MRI examining the pituitary gland within 2 months. Four (9.3%) had initial reporting consistent with hypophysitis. Upon re-examination by an MRI-Fellowship trained radiologist, a further 6 (total 10, 23%) had acute hypophysitis changes. Among the control group, 45 of 46 individuals had an MRI within 2 months of normal pituitary biochemistry. All initial MRI reports were normal, but upon review 1 (2.2%) had acute hypophysitis abnormalities, with a significant difference between groups (10/43 vs 1/45, p = 0.003). Within the control group, a further 10 (22%) individuals had an atrophic pituitary and/or empty sella. No other significant pituitary pathology, including pituitary metastasis, was identified.

Although changes were observed in a minority of patients with hypophysitis, MRI provides minimal additional clinically meaningful information, so it could be reserved for atypical cases or those with persisting symptoms despite adequate supplementation.

Immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm of non-small cell lung cancer (NSCLC) over the last decade. Despite notable therapeutic advancements in responders, the response rate remains limited owing to the immunosuppressive tumor microenvironment (TME). Therefore, to improve the efficacy of ICIs, it is essential to explore alternative targets or signals that mediate immunosuppression. Immunoglobulin-like transcript (ILT) 5 is a negative regulator of immune activation in myeloid cells. However, the expression and function of ILT5 in NSCLC remain unknown. Here, we found that ILT5 was highly expressed in tumor-associated macrophages (TAMs) of NSCLC tissues and predicted poor patient survival. Functionally, ILT5 induces the M2-like polarization of TAMs, which subsequently decreases the density of T cells, and increases FOXP3+T cell accumulation, leading to an immunosuppressive TME. The combination of ILT5 expression with M2-like TAM density is a more reliable biomarker of patient survival than ILT5 expression alone. ILT5 knockout mitigates the reprogramming of TAM and T cell subsets toward immunosuppressive phenotypes and inhibits tumor growth in vivo. These findings highlight that ILT5 is a potential immunotherapeutic target and a promising prognostic biomarker for NSCLC.

Programmed cell death protein 1 (PD-1) is a critical immune checkpoint receptor that suppresses immune responses largely through its interaction with PD-L1. Tumors exploit this mechanism to evade immune surveillance, positioning immune checkpoint inhibitors targeting the PD-1/PD-L1 axis as groundbreaking advancements in cancer therapy. However, the overall effectiveness of these therapies is often constrained by an incomplete understanding of the underlying mechanisms. Recent research has uncovered the pivotal role of various post-translational modifications (PTMs) of PD-1, including ubiquitination, UFMylation, phosphorylation, palmitoylation, and glycosylation, in regulating its protein stability, localization, and protein-protein interactions. As much, dysregulation of these PTMs can drive PD-1-mediated immune evasion and contribute to therapeutic resistance. Notably, targeting PD-1 PTMs with small-molecule inhibitors or monoclonal antibodies (MAbs) has shown potential to bolster anti-tumor immunity in both pre-clinical mouse models and clinical trials. This review highlights recent findings on PD-1's PTMs and explores emerging therapeutic strategies aimed at modulating these modifications. By integrating these mechanistic insights, the development of combination cancer immunotherapies can be further rationally advanced, offering new avenues for more effective and durable treatments.

Liver cancer, more specifically hepatocellular carcinoma (HCC), is a global health issue and one of the dominant causes of cancer death around the world. In the past few decades, remarkable advances have been achieved in the systemic therapy of HCC. Immune checkpoint inhibitors (ICIs) have become a therapy mainstay for advanced HCC and have shown promise in the neoadjuvant therapy before resection. Despite these significant advancements, the compositions and functions of the immune system occur various alterations with age, called "immunosenescence", which may affect the antitumor effects and safety of ICIs, thus raising concerns that immunosenescence may impair elderly patients' response to ICIs. Therefore, it is important to learn more about the immunosenescence characteristics of elderly patients. However, the real-world elderly HCC patients may be not accurately represented by the elderly patients included in the clinical trials, affecting the generalizability of the efficacy and safety profiles from the clinical trials to the real-world elderly patients. This review summarizes the characteristics of immunosenescence and its influence on HCC progression and immunotherapy efficacy as well as provides the latest progress in ICIs available for HCC and discusses their treatment efficacy and safety on elderly patients. In the future, more studies are needed to clarify the mechanisms of immunosenescence in HCC, and to find sensitive screening tools or biomarkers to identify the patients who may benefit from ICIs.

As a promising anti-tumor modality, photodynamic immunotherapy (PDIT) has been applied for the treatment of many solid tumors. However, tumor hypoxic condition and immunosuppressive microenvironment severely limit the treatment outcome of PDIT. Here, we have designed a hairpin tetrahedral DNA nanostructure (H-TDN)-modified bifunctional cascaded Pt single-atom nanozyme (PCFP@H-TDN) with encapsulation of the photosensitizer. The PCFP@H-TDN have dual enzyme-like activities, which can catalyze cascade reactions to generate sufficient O2, reversing the tumor hypoxia and thereby significantly enhancing the anti-tumor effect of PDIT. Meanwhile, H-TDN can not only block the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) recognition pathway but also target the delivery of PD-L1 antisense oligonucleotides to reduce overall PD-L1 protein expression on the surface of tumor cells, achieving the combination of PD-1/PD-L1 pathway blockade and PD-L1 protein expression silencing. The dual-depressing PD-L1 significantly improves immune checkpoint blockade efficacy. In vivo studies have shown that the constructed PCFP@H-TDN synergistically improved the therapeutic effect of tumors in a multimodal manner through enhancing tumor immunogenicity and upregulating immune cell infiltration at the tumor site. This study provides an efficient nanomedicine to enhance PDIT by depressing PD-L1 and regulating hypoxia.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment. However, abnormal tumor vasculature and excess lactate contribute to tumor immunosuppression and confer resistance to ICB therapy, seriously limiting its clinical application. Here, we have developed a bioresponsive nanoreactor, ALMn, which consists of hollow manganese dioxide nanoparticles with encapsulation of lactate oxidase and L-Arginine, to overcome immunosuppression and sensitize ICB therapy. In the tumor microenvironment, lactate oxidase catalyzes lactate to produce hydrogen peroxide, which subsequently oxidizes L-Arginine to generate nitric oxide for vascular normalization. Through cascade reactions, ALMn effectively depletes excess lactate and normalize tumor vasculature, reshaping the immunosuppressive phenotype to an immune-activated one. Transcriptomics and immunological analyses prove that ALMn facilitates the infiltration and activation of effector cells, further potentiating antitumor immunity. Consequently, ALMn sensitizes anti-PD-L1 therapy, significantly suppressing tumor growth with an 83.7 % suppression, and prolonging the survival of mice, with the median survival time increasing from 29.5 days to 54.5 days. Our study demonstrates that ALMn effectively alleviates tumor immunosuppression and synergizes with anti-PD-L1, which shows promise in boosting ICB therapy.

The prevalence of Programmed death ligand 1 (PD-L1) expression in the population of NSCLC patients and blocking the PD1/PD-L1 pathway by inhibiting the PD-1 receptor on immune cells or the PD-L1 ligand on tumour and/or immune cells can inhibit tumour growth. EFBALite algorithm that enables efficient and cost-effective selection of aptamers, expediting the process. Here, we present the development, computational validation, and in vitro analysis of NSCLC of DNA aptamers targeting PD-L1. The Gibbs free energy of two anti-PD-L1 aptamers, Apta35 and Apta90 with -3.06 and - 2.4 kcal/mol respectively. The docking score for Apta35 was -272.3 and 1171.765 for HDOCK and ZDOCK respectively. Further, the Apta35 was taken for the in vitro studies as it was more stable and incubated with NCI-H460. Initially, we confirmed the binding of the TAMRA-labelled Apta35 to the NCI-H460 cell surface through microscopic imaging and further confirmed through FACS analysis. Further experimental results showed that the Apta35 treated along with the act-T cells group reduced the percentage of viability (28 ± 3.5), increased toxicity, and reduced count of NCI-H460 cells when compared with the cells treated only with the act-T cells concerning the treatment to 50 nM concentration. In summary, targeting PD-L1 with a specific aptamer provides an innovative strategy for targeting NSCLC. Apta35 aptamer showed no significant toxicity in the BALB/c nude mice while it was injected every 2 days for a total of 12 days of treatment.

Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. In this study, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti-PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell-derived IFNγ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK-STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the antitumor efficacy of anti-PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate, suppressed the tumor antigen presentation and cross-priming ability of dendritic cells, resulting in the impairment of antigen-specific T-cell antitumor responses. In summary, these findings identify an IFNγ-dependent immunometabolic mechanism of anti-PD-1 resistance, providing a promising strategy for combination therapy. Significance: Elevated itaconate production by macrophages induced by IFNγ is a critical negative feedback immunoregulatory metabolic response to anti-PD-1 immunotherapy that inhibits the cross-priming function of dendritic cells and confers immunotherapy resistance.

Modulating cancer-related chronic inflammation (CCI) is essential to reverse the immunosuppressive tumor microenvironment (TME) for improved therapeutic outcomes. However, the complexity and dynamism of inflammatory processes within the TME pose formidable challenges. Here, we identify senescent tumor cells as a novel "nest"-like target and design a tailored nanotuner that transforms these cells from adversaries to allies in TME remodeling. Specifically, this nanotuner targets metabolic abnormalities and initiates cascading artificial reactions via chemiluminescence resonance energy transfer mechanisms, which trigger self-initiated and self-sustaining photodynamic processes for boosted 1O2, converting cellular senescence into pyroptosis. Such conversion fosters multifaceted immune activation, including blocking CCI networks, downregulating PD-L1, and enhancing dendritic cell maturation and T-cell recruitment in tumors. Assessments in two tumor models further demonstrate its durable antitumor effects against primary and distant solid tumors when combined with a PD-1 blockade. This work provides a paradigm shift for novel insights into tumor development and immunoregulatory tactics.

The PD-L1/PD-1 pathway is crucial for immune regulation and has become a target in cancer immunotherapy. However, in order to improve patient selection for immune checkpoint blockade (ICB) therapies, better selection criteria are needed. This study explores how the N-glycosylation of PD-L1 affects its interaction with PD-1 and ICB efficacy, focusing on its four N-linked glycosylation sites: N35, N192, N200, and N219.

Human PD-L1 glycosylation mutants-at each individual site or at all four sites together (Nx4)-were tested for their functional interaction with PD-1 using an artificial immune checkpoint reporter assay (IcAR-PD1). The blocking efficacy of anti-PD-L1 and anti-PD-1 antibodies was evaluated using human breast cancer cell lines (MDA-MB231 and MCF7), as well as A375 melanoma and A549 lung carcinoma cells expressing the glycosylation mutants. Results were validated through ex vivo activation and cytotoxicity assays using human CD8+ T cells.

The binding of the PD-L1N35A mutant to PD-1 was not effectively blocked by anti-PD-L1 and anti-PD-1 ICBs. In contrast, high blocking efficacy of PD-L1 binding to PD-1 was obtained at minimal ICB concentrations when PD-L1 did not express any glycosylation site (PD-L1Nx4 mutant). The PD-L1N35A mutant produced elevated levels of PD-L1 as a soluble (sPD-L1) and extracellular vesicles (EV)-bound molecule; in contrast, the PD-L1Nx4 mutant had lower sPD-L1 and EV levels. PD-L1 glycosylation status influenced the ability of PD-L1 interactions with PD-1 to down-regulate T-cell activation and cytotoxicity, with the PD-L1N35A mutant showing the lowest levels of T cell functions and the PD-L1Nx4 mutant the highest.

The N-glycosylation of PD-L1 at all four sites interferes with the ability of anti-PD-L1 and anti-PD-1 ICBs to block PD-L1 interactions with PD-1; in contrast, glycosylation at the N35 site enhances ICB blocking efficacy. These effects are connected to the ability of sPD-L1 to compete with ICB binding to PD-L1 or PD-1. Thus, assessing PD-L1 glycosylation, beyond expression levels, could improve patient stratification and outcomes.

The barriers from cancer-associated fibroblasts (CAFs) have diminished the clinical efficacy of immunotherapy for triple-negative breast cancer (TNBC). The obstacles from CAFs often result in poor drug penetration, constrained cytotoxic T lymphocyte infiltration, and an immunosuppressive microenvironment. Herein, chondroitin sulfate (CS) was engineered to conjugate dasatinib (DAS), a tyrosine kinase inhibitor, via the cathepsin B (CTSB)-responsive GFLG linker to produce CS-GFLG-DAS (CGD), which could be employed to reverse the CAF phenotype and regulate the biosynthesis of extracellular matrix (ECM), thus enhancing the efficacy of immune checkpoint blockade (ICB) therapy. Upon reaching the tumor site, DAS released from CGD in response to overexpressed CTSB in the tumor microenvironment could transform CAFs into a quiescent state instead of killing them to prevent CAFs from producing abundant ECM, thereby promoting deep penetration of CGD to effectively kill tumor cells. In addition, ECM remodeling facilitated tumor infiltration of cytotoxic T lymphocytes, synergistically enhancing the anti-PD-1 efficacy in the 4T1 tumor-bearing mice. In summary, this prodrug enhanced deep drug penetration and therapeutic sensitivity of anti-PD-1 by regulating CAFs, providing new insights into optimizing immunotherapy in treating fibrotic tumors via nanomedicine.

V-domain Ig suppressor of T cell activation (VISTA) is a recently characterized as immune checkpoint regulator with critical roles in modulating immune responses across pathological contexts. In cancer, VISTA contributes to immune evasion by sustaining an immunosuppressive tumor microenvironment, emerging as a promising target for immunotherapeutic intervention. In contrast, in autoimmune diseases, VISTA preserves peripheral immune tolerance and suppresses aberrant immune activation, thereby preventing tissue destruction. This functional dichotomy reflects the complexity of VISTA-mediated signaling, which is modulated by cellular context, microenvironmental cues, and disease stage. Recent studies have elucidated key aspects of VISTA biology, including its structural features, ligand interactions, and context-dependent expression patterns. VISTA operates as a co-inhibitory molecule in cancer, while exerting co-stimulatory or regulatory effects in autoimmunity. This review provides a comprehensive overview of VISTA's discovery, molecular mechanisms, and dual roles in cancer and autoimmune pathogenesis. Furthermore, the current status of VISTA-targeted therapeutic strategies is critically examined, highlighting the translational challenges posed by discrepancies between preclinical models and clinical trial outcomes. Finally, the potential of targeting VISTA within the broader paradigm of immune checkpoint plasticity is discussed, with emphasis on overcoming compensatory immune resistance to enhance therapeutic efficacy. A deeper mechanistic understanding of VISTA is essential for the rational design of future immunomodulatory therapies tailored to specific disease contexts.

Immunotherapy is a potential strategy to suppress the postoperative recurrence and metastasis of triple-negative breast cancer (TNBC). However, the excessive accumulation of kynurenine (Kyn) leads to immunosuppressive tumor microenvironment (TME) and impedes immunotherapeutic efficacy. Herein, a two-pronged approach through "Kynurenine Starvation Therapy" is proposed based on the in-situ hydrogel implantation for postsurgical treatment of TNBC. The hydrogel is constructed via Schiff base reaction between oxidized dextran (ODEX) and 8-arm poly(ethylene glycol) amine (8-arm PEG-NH2), which exhibits excellent biocompatibility and gradual biodegradability. The indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG919 and kynureninase (KYNase) are noncovalently loaded into the hydrogel to prepare NLG919 + KYNase@Gel. The obtained hydrogel can sustainably release NLG919 and KYNase to synergistically deplete Kyn, thereby reversing immunosuppression to enhance the antitumor immunity within TME through "Kynurenine Starvation Therapy". Moreover, a single implantation of NLG919 + KYNase@Gel not only effectively inhibits the postoperative recurrence and metastasis in 4 T1 tumor-bearing mice, but also restrains the growth in an orthotopic TNBC mouse model. These findings highlight an innovative strategy to reinforce the antitumor immune response for the treatment of postsurgical TNBC.

Chemoimmunotherapy is an alternative treatment against cancers. Platinum(IV) complexes FMP and DFMP, coupling formononetin derivative as axial ligand(s), were designed to suppress triple-negative breast cancer (TNBC) by activating death receptors (DRs) and natural killer (NK) cells. These complexes show great potential to overcome the resistance of TNBC to chemotherapy by inducing both intrinsic and extrinsic apoptosis in cancer cells. Particularly, FMP with one axial formononetin derivative not only induced the caspase-3-dependent intrinsic apoptosis but also upregulated the expression of DRs and caspase-8, triggered the extrinsic apoptosis, and enhanced the cytotoxic ability of NK92 cells. Moreover, FMP increased the release of granzyme B, restrained the proliferation and differentiation of myeloid-derived suppressor cells, and the secretion of IL-10, thus inhibiting the TNBC in vitro and in vivo. The results demonstrate that FMP overcomes the chemoresistance and immune escape of TNBC through a new mechanism involving the synergy of chemotherapy and immunotherapy.

Urothelial carcinoma (UC) treatment has been transformed by immunotherapy and antibody-drug conjugates (ADCs). This review evaluates the current evidence for these approaches and identifies future directions.

We conducted a structured review of clinical trials, meta-analyses, and guidelines published until early 2025.

Immune checkpoint inhibitors have established benefits across multiple settings: post-platinum therapy (pembrolizumab, nivolumab), maintenance therapy (avelumab), adjuvant settings for high-risk muscle-invasive disease (nivolumab), and BCG-unresponsive non-muscle-invasive disease (pembrolizumab). Enfortumab vedotin (targeting Nectin-4) has proven effective in post-platinum/post-immunotherapy. Most significantly, enfortumab vedotin plus pembrolizumab has redefined first-line treatment with unprecedented survival benefits (median OS 31.5 months vs. 16.1 months with chemotherapy; HR 0.47), and nivolumab plus gemcitabine-cisplatin improved outcomes in cisplatin-eligible patients. Key challenges include managing unique toxicity profiles, optimizing treatment sequencing, and developing reliable biomarkers.

Combination approaches offer the most promising path forward, with future research needed on resistance mechanisms, biomarker development, and expanding these therapies to earlier disease stages.

Organoid models are powerful tools for evaluating cancer immunotherapy that provide a more accurate representation of the tumour microenvironment (TME) and immune responses than traditional models. This review focuses on the latest advancements in organoid technologies, including immune cell co-culture, 3D bioprinting, and microfluidic systems, which enhance the modelling of TME and facilitate the assessment of immune therapies such as immune checkpoint inhibitors (ICIs), CAR-T therapies, and oncolytic viruses. Although these models have great potential in personalised cancer treatment, challenges persist in immune cell diversity, long-term culture stability, and reproducibility. Future developments integrating artificial intelligence (AI), multi-omics, and high-throughput platforms are expected to improve the predictive power of organoid models and accelerate the clinical translation of immunotherapy.

Poly(ADP-ribose) polymerase inhibitors (PARPis) are a class of agents targeting DNA damage repair that have become standard therapy for epithelial ovarian cancer (EOC) and multiple other solid tumors. In addition to targeting DNA damage repair, PARPis actively modulate antitumor immune responses, with efficacy being partially dependent on T cell activity. Here, we found that patient T cells sustain DNA damage during PARPi treatment, which reduces treatment efficacy. Leveraging paired pre- and posttreatment tumor samples from a clinical trial of patients with EOC treated with neoadjuvant niraparib as monotherapy, we showed that the PARPi caused DNA damage, slowed proliferation, and increased apoptosis in T cells, which we validated both in vitro and in mouse models. A genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) knockout screen in primary human T cells identified PARP1 as the principal mediator of PARPi-induced T cell death. T cell-specific deletion of PARP1 or mutating Parp1 at its binding sites in transgenic mice led to reduced T cell DNA damage during PARPi treatment, resulting in improved efficacy of PARPis, alone or in combination with immune checkpoint inhibition. We then engineered PARPi-tolerant CAR T cells using cytosine base editing, which decreased PARPi-induced PARP1 trapping and led to reduced PARPi-induced DNA damage, resulting in superior antitumor efficacy in xenograft models compared with parental CAR T cells. This study highlights the relevance of PARPi-induced DNA damage to T cells and suggests opportunities to improve the efficacy of PARPis as monotherapy or in combination with immunotherapy.

We have previously shown that immune checkpoint receptors, including PD-1, are upregulated on T cells at the time of their activation, and that blockade of these receptors can improve the efficacy of antitumor vaccines. In the present study, we sought to determine whether, and by what mechanisms, the timing of PD-1 blockade with respect to vaccination affects antitumor T cell function.

TRAMP-C1 or E.G7-OVA tumor-bearing mice received PD-1 blockade at different timing intervals with a tumor-associated antigen vaccine. Tumor growth, survival, and immune-infiltrating populations were assessed. In vitro models of T cell activation using OT-I T cells and PD-(L)1 axis disruption with a PD-1 blocking antibody or PD-L1KO dendritic cells were used.

Mice receiving PD-1 blockade at the time of T cell activation with vaccine had better antitumor outcomes in comparison to mice receiving PD-1 blockade before or after immunization. T cells activated in vitro in the presence of PD-(L)1 axis disruption had a more differentiated, functional phenotype with decreased CD28 and CCR7 expression and increased production of the Tc1 cytokines IL-2, TNFα, and IFNγ. Intriguingly, a small subset of undifferentiated cells (CD28+) was of a stem-like Tc17 phenotype (IL-17α+, TCF1+). Tumor-bearing mice receiving T cells activated in the presence of PD-(L)1-axis disruption had better antitumor outcomes and a greater number of complete responses.

These data indicate that PD-1 blockade, when used with antitumor vaccines, acts primarily at the time of T cell activation, not exclusively within the tumor microenvironment. Consequently, PD-1 blockade may be best used when delivered concurrently with T cell activating agents such as vaccines.

Cognitive difficulties are frequently reported after cancer treatments, such as chemotherapy or hormone therapy, and have a negative impact on patients' quality of life. Recently, some studies have shown that new cancer treatments, such as immunotherapy agents, can induce cognitive changes.

This review presents the central neurological immune adverse events of immunotherapy treatments including Immune Checkpoint Inhibitors (ICI) and Chimeric Antigen Receptor (CAR) T-cell therapy. The physiopathological mechanisms and risk factors are developed and clinical studies on immunotherapy agents and cognition (among adult patients, using validated questionnaires and/or cognitive tests), psychological factors and quality of life were presented.

Neurological toxicities are frequently observed with CAR-T cell therapies at acute stage, such as the immune effector cell-associated neurotoxicity syndrome (ICANS), inducing cognitive disorders such as disorientation and aphasia. However, few studies have accurately assessed the impact of immunotherapy on cognition. The methodology of these studies is heterogeneous and they mainly included nonspecific self-report questionnaires of cognitive complaints. Variable results have been obtained concerning the cognitive impact of ICI and CAR-T cell several months following immunotherapy: overall, while some studies reported cognitive difficulties (mainly processing speed and executive functions), the majority has not. Although anxiety and depression are frequently reported in patients treated with ICI or CAR-T cells, these symptoms tend to decrease after the start of immunotherapy. The current neurobiological investigations are too fragmentary to explain neurological symptoms and potential cognitive alteration, but neuroinflammation, vascular inflammation, brain blood barrier disruption, and immune cell brain infiltration would constitute common mechanisms relayed by CAR-T and to a lesser degree, ICI.

Acute neurological toxicities following CAR-T cell therapies are a major issue. Further studies are needed to better assess cognitive difficulties after the initiation of immunotherapy, in particular ICI, to better understand the physiopathology, including imaging studies, and risk factors.

Hematopoietic progenitor kinase 1 (HPK1), a negative regulator of T-cells, B-cells, and dendritic cells, has gained attention in antitumor immunotherapy research over the past decade. No HPK1 inhibitor has yet reached clinical approval, largely due to selectivity and drug-like limitations. Leveraging the available structural insights into HPK1, we conducted a rational hit identification using a structure-based virtual screening of over 600,000 drug-like molecules from ASINEX and OTAVA databases. A series of molecular docking studies, in vitro kinase assays, and molecular dynamics simulations were conducted to identify viable HPK1 inhibitor hits. This approach resulted in two promising novel hit scaffolds, 4H-Pyrido[1,2-a] thieno[2,3-d] pyrimidin-4-one (ISR-05) and quinolin-2(1H)-one (ISR-03), neither of which has previously been reported as an HPK1 inhibitor. ISR-05 and ISR-03 exhibited IC50 values of 24.2 ± 5.07 and 43.9 ± 0.134 µM, respectively, in kinase inhibition assays. These hits constitute tractable starting points for future hit-to-lead optimization aimed at developing more effective HPK1 inhibitors for cancer therapy.

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and PD-1 have shown remarkable antitumor efficacy, but can also cause immune-related adverse events, including checkpoint inhibitor-induced liver injury (ChILI). This multi-omic study aimed to investigate changes in blood samples from treated cancer patients who developed ChILI. PBMCs were sequenced for by transcriptomic and T cell receptor repertoire (bulk and single-cell immune profiling), and extracellular vesicle (EV) enrichment from plasma was analyzed by mass spectroscopy proteomics. Data were analyzed by comparing the ChILI patient group to the control group who did not develop ChILI and by comparing the onset of ChILI to pre-ICI treatment baseline. We identified significant changes in T cell clonality, gene expression, and proteins in peripheral blood mononuclear cells (PBMCs) and plasma in response to liver injury. Onset of ChILI was accompanied by an increase in T cell clonality. Pathway analysis highlighted the involvement of innate and cellular immune responses, mitosis, pyroptosis, and oxidative stress. Single-cell RNA sequencing revealed that these changes were primarily found in select T cell subtypes (including CD8 + effector memory cells), while CD16 + monocytes exhibited enrichment in metabolic pathways. Proteomic analysis of plasma extracellular vesicles showed enrichment in liver-associated proteins among differentially expressed proteins. Interestingly, an increase in PBMC PD-L1 gene expression and plasma PD-L1 protein was also found to be associated with ChILI onset. These findings provide valuable insights into the immune and molecular mechanisms underlying ChILI as well as potential biomarkers of ChILI.Trial registration number NCT04476563.

CD169+ macrophages in lymph nodes (LNs) activate cytotoxic T lymphocytes (CTLs), which play a crucial role in anticancer immunity, through antigen presentation and co-stimulation by CD169. Interferon alpha (IFNα) is capable of inducing the CD169+ phenotype of macrophages; however, its clinical applications have been hindered by pharmacokinetic limitations-low LN distribution and an inability to target macrophages. To overcome these issues, this study genetically fused mouse IFNα (mIFNα) with mannosylated mouse serum albumin (Man-MSA), and investigated the antitumor effects of the hybrid protein (Man-MSA-mIFNα) or its add-on effects with programmed death-ligand 1 (PD-L1) blockade.

To confirm the possibility of CD169+ macrophage-mediated T cell priming, positional information about individual immune cells in LNs of cancer patients was obtained. Traits of Man-MSA-mIFNα, which was prepared using Pichia pastoris to form the high-mannose structure, were characterized by several physicochemical methods. To evaluate the lymphatic drainage of Man-MSA-mIFNα, radioiodine or Cy5-labeled Man-MSA-mIFNα was subcutaneously administered in mice, and then the radioactivity or fluorescence in LNs was analyzed. CD169-diphtheria toxin (DT) receptor (CD169-DTR) mice in which LN CD169+ macrophages can be depleted by DT injection were used to verify whether the antitumor effect of Man-MSA-mIFNα is dependent on LN CD169+ macrophages.

Multiplex tissue imaging predicted close proximity of CD169+ macrophages and T cells and positive correlation between the number of CD169+ macrophages and T cells in neighborhoods in LNs of cancer patients. Physicochemical analyses showed that Man-MSA-mIFNα was formed from the fusion of the intact Man-MSA and mIFNα. Man-MSA-mIFNα efficiently induced the CD169+ phenotype of macrophages by its high LN distribution and macrophage-targeting capability, and significantly exerted antitumor activity through CD8+ T cell activation in the LNs, whereas its antitumor effects were canceled in CD169-DTR mice. Finally, combination therapy with PD-L1 blockade markedly suppressed tumor growth in MB49-bearing mice, which exhibit resistance to PD-L1 blockade monotherapy.

The present study successfully designed and developed Man-MSA-mIFNα, which efficiently induces the CD169+ phenotype in LN macrophages, contributing to the antitumor immunity. The findings suggest that our novel strategy targeting CD169⁺ macrophages could be a promising immunotherapy for cancer patients who are unresponsive to immune checkpoint inhibitors.

The composition of the microbiota in patients has been shown to correlate with cancer progression and response to therapy, highlighting unique opportunities to improve patient outcomes. In this review, we discuss the challenges and advancements in understanding the chemical mechanisms of specific microbiota species, pathways, and molecules involved in cancer progression and treatment. We also describe the modulation of cancer and immunotherapy by the microbiota, along with approaches for investigating microbiota enzymes and metabolites. Elucidating these specific microbiota mechanisms and molecules should offer new opportunities for developing enhanced diagnostics and therapeutics to improve outcomes for cancer patients. Nonetheless, many microbiota mechanisms remain to be determined and require innovative chemical genetic approaches.