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PubMed2026

Pre-treatment polyfunctionality percentage (PFA) of CD8+ T cells is associated with development of immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICIs).

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have improved cancer survival, but immune-related adverse events (irAEs) occur frequently and can have devastating consequences. There are no validated methods to evaluate risk of irAEs prior to initiation of ICIs. MATERIALS AND METHODS: We conducted a pilot study evaluating the ability of blood-based, single-cell secretomic analysis to characterize irAEs. A total of 10 patients with thoracic malignancies who were scheduled to receive ICIs were enrolled. Each patient had a pre-ICI blood sample drawn as well as a sample at the time of irAE development or 12 weeks after ICI initiation, whichever came first. Utilizing IsoPlexis's IsoLight system, polyfunctionality percentages (PFAs) and strength indices (PSIs) were analyzed for CD4+ and CD8+ T cells. RESULTS: Five patients developed irAEs and 5 patients did not develop irAEs. Pre- and post-ICI CD8+ T cell PFA was significantly elevated in patients who developed irAEs compared with those who did not (p = 0.017 and p = 0.014, respectively). CONCLUSIONS: In this pilot study, pre-ICI CD8+ T cell PFA was associated with development of irAEs. While this is a pilot study, this is a first step toward developing a blood-based, streamlined assay to assess risk of irAEs prior to initiation of ICIs. Validation in larger cohorts is warranted.

Humans↗

PubMed2025

Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and beyond.

BACKGROUND: Integration of immune checkpoint inhibitors (ICIs) with non-immune therapies relies on identifying combinatorial biomarkers, which are essential for patient stratification and personalized treatment. METHODS: We analyzed genomic and transcriptomic data from pretreatment tumor samples of 342 melanoma patients treated with ICIs to identify mutations and expression signatures associated with ICI response and survival. External validation and mechanistic exploratory analyses were conducted in two additional datasets to assess generalizability. RESULTS: Responders were more likely to have received anti-PD-1 therapy rather than anti-CTLA-4 and exhibited a higher tumor mutation burden (both P < 0.001). Mutations in the dynein axonemal heavy chain (DNAH) family genes, specifically DNAH2 (P = 0.03), DNAH6 (P < 0.001), and DNAH9 (P < 0.01), were enriched in responders. The combined mutational status of DNAH 2/6/9 effectively stratified patients by progression-free survival (hazard ratio [HR]: 0.69; 95% confidence interval [CI] 0.51-0.92; P = 0.013) and overall survival (HR: 0.58; 95% CI 0.43-0.78; P < 0.001), with consistent association observed in the validation cohort (HR: 0.28; 95% CI 0.12-0.61; P < 0.001). DNAH-altered melanomas exhibited upregulation of chemokine signaling, cytokine-cytokine receptor interaction, and cell cycle-related pathways, along with elevated expression of immune-related signatures in interferon signaling, cytolytic activity, T cell function, and immune checkpoints. Using LASSO logistic regression, we identified a 26-gene composite signature predictive of clinical response, achieving an area under the curve (AUC) of 0.880 (95% CI 0.825-0.936) in the training dataset and 0.725 (95% CI 0.595-0.856) in the testing dataset. High-risk patients, stratified by the expression levels of a 13-gene signature, demonstrated significantly shorter overall survival in both datasets (HR: 3.35; P < 0.001; HR: 2.93; P = 0.002). CONCLUSIONS: This analysis identified potential molecular determinants of response and survival to ICI treatment. Insights from melanoma biomarker research hold significant promise for translation into other malignancies, guiding individualized anti-tumor immunotherapy.

Humans↗

PubMed2026

Immune Checkpoint Inhibitor-related Adverse Events in Publicly Accessible United States Malpractice Records: A Systematic Legal Database Review, 2015 to 2026.

OBJECTIVES: By 2023, an estimated 56.7% of US patients with advanced or metastatic cancer were eligible for immune checkpoint inhibitor (ICI) therapy. Grade 3 to 4 immune-related adverse events (irAEs) occur in ∼14% to 21% of patients depending on regimen, yet publicly accessible malpractice records involving ICI administration or irAE management have not been systematically described. METHODS: We searched Lexis+ and Westlaw Advantage for publicly accessible US malpractice records filed from January 1, 2015, through March 31, 2026. Sources included jury verdicts and settlement databases, federal and state dockets, and briefs, pleadings, and motions databases. Cases were included only when ICI administration, indication selection, toxicity counseling, toxicity recognition, toxicity monitoring, or irAE management was causally central to the alleged negligence. RESULTS: Among 38 legal matters identified after cross-platform deduplication, 4 met eligibility criteria. These matters reflected 4 pleaded negligence theories: inappropriate ICI indication, toxicity counseling and informed-consent failure, irAE mismanagement, and treatment-related multiorgan toxicity. Publicly visible irAE-centered malpractice records were rare relative to the clinical burden, but the data do not support a national litigation incidence estimate. CONCLUSIONS: Publicly accessible irAE-centered malpractice records appear rare. As ICI use expands, litigation risk may increasingly focus on indication documentation, individualized toxicity counseling, and structured monitoring.

immune checkpoint inhibitors↗

PubMed2026

Spatial proteomics reveals four-stage molecular evolution in cancer immunotherapy-related gastritis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet immune-related adverse events (irAEs) including immunotherapy-related gastritis (IRAEG) pose significant clinical challenges-often necessitating treatment interruption that may compromise antitumor efficacy. IRAEG presents with atypical symptoms, lacks specific biomarkers, and shows histopathological overlap with other forms of gastritis, complicating diagnosis and management. Despite increasing clinical recognition, a systematic understanding of spatial molecular alterations across the full disease course remains limited. Here, we used spatial proteomics to map the molecular landscape of IRAEG during disease progression and to define stage-specific patterns of molecular evolution relevant to cancer immunotherapy management. METHODS: We analyzed tissue samples from seven patients, including four non-immunotherapy-related gastritis controls and three cancer patients who developed IRAEG following ICI therapy for solid tumors, sampled longitudinally across four disease stages: baseline (G1), acute severe inflammation (G2), early recovery (G3), and complete recovery (G4). Using laser capture microdissection coupled with data-independent acquisition mass spectrometry, we profiled 177 spatially resolved gastric tissue regions. Multiplex immunohistochemistry and immunofluorescence characterized features of the immune microenvironment, while Gene Ontology, KEGG pathway analysis, Gene Set Variation Analysis, and xCell inference enabled functional, metabolic, and immune profiling. Key immune and NET-related findings were further validated by multiplex immunofluorescence in an independent, expanded cohort of IRAEG and non-immunotherapy-related gastritis samples. RESULTS: IRAEG was characterized by widespread HLA molecule activation and enhanced antigen processing, resembling the immune phenotype observed in organ transplant rejection. The acute G2 stage exhibited excessive neutrophil extracellular trap formation, profound metabolic suppression, and collapse of immune homeostasis-features that may inform early intervention strategies to preserve ICI treatment continuity. During early recovery (G3), inflammatory injury transitioned toward repair, marked by activation of fatty acid metabolism and PPAR signaling. Notably, even at complete clinical recovery (G4), more than 1,000 proteins remained differentially expressed, reflecting sustained enhancement of metabolic and immune functions and establishing a distinct molecular "memory" state with implications for ICI rechallenge decisions. CONCLUSIONS: These findings define four molecularly distinct stages of IRAEG progression and recovery. The stage-specific signatures identified here serve as candidate biomarkers for diagnosis, disease staging, and therapeutic response assessment, and may guide clinical decisions regarding irAE management, treatment modification, and safe ICI rechallenge to support continued antitumor therapy.

Humans↗

PubMed2025

Genetic haplotypes in VWA8, OSBPL6, and ADAMTS9-AS2 are associated with immune-related adverse effects in ICI-treated patients with cancer.

BACKGROUND: Immune-related adverse events (irAEs) remain largely unpredictable, potentially affecting multiple organ systems and occurring at almost any point during and even occasionally after immune checkpoint inhibitor (ICI) treatment. To identify populations at risk for these immune-mediated toxicities, we analyzed genetic characteristics and immune markers associated with clinically significant irAEs. METHODS: We carried out a genome-wide association study on 373 white patients receiving ICI treatment. We identified single nucleotide polymorphisms associated with irAEs. Blood cytokine profiling and peripheral blood mononuclear cell RNA sequencing were performed at pretreatment baseline and 6-8 weeks after ICI initiation. Findings were validated in two external cohorts. RESULTS: We identified genetic haplotypes in VWA8 (Von Willebrand Factor A Domain Containing 8), OSBPL6 (Oxysterol Binding Protein Like 6), and ADAMTS9-AS2 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif 9 Antisense RNA 2) associated with grade ≥2 irAEs. Patients carrying risk haplotypes for one or more genes exhibited significantly greater rates of grade ≥2 (OR 3.02; 95% CI 1.83 to 5.02; p<0.001), grade ≥3 (OR 3.59; 95% CI 1.93 to 6.64; p<0.001), and multiple type irAE (OR 2.60; 95% CI 1.53 to 4.39; p<0.001). Serum CCL3 levels were significantly elevated in individuals carrying risk haplotypes (p=0.03). Gene expression analysis demonstrated activated autoimmune and inflammatory pathways in the genetic risk group. CONCLUSIONS: Novel polymorphisms in VWA8, OSBPL6, and ADAMTS9-AS2 may impact immune pathways, promote inflammation, potentiate autoimmune phenotypes, and convey risk of irAE in ICI-treated patients.

Humans↗

PubMed2026

Targeting USP22 reprograms the tumor microenvironment and sensitizes KRAS/p53-driven lung cancer to anti-PD-1 immunotherapy.

RATIONALE: Ubiquitin-specific peptidase 22 (USP22), a deubiquitinase and component of the "Death-from-Cancer" 11-gene signature, is overexpressed in multiple malignancies and linked to recurrence, therapy resistance, and poor prognosis. Its role in KRAS/p53-driven lung cancer and the response to immune checkpoint inhibitors (ICIs) remains poorly defined. Here, we investigated USP22 as a potential therapeutic target in KRAS/p53-driven lung cancer. METHODS: A conditional Usp22 knockout (Usp22-KO) was generated in the KRASG12D; p53-/- (KP) mouse model. Cancer progression was monitored by micro-computed tomography (micro-CT). Multiplex immunofluorescence (mIF), RNA sequencing, and spatial transcriptomics profiled cancer and tumor microenvironment (TME) changes. Responses to anti-PD-1/PD-L1 therapies were compared between KP and Usp22-KO KP (KPU-) lung cancers. RESULTS: USP22 was highly expressed in early-stage KRAS/p53-driven mouse lung cancers and strongly correlated with proliferation marker Ki67. Usp22 deletion suppressed cancer growth, prolonged survival, and promoted cancer differentiation. Spatial transcriptomics and mIF revealed reduced CD206+ M2 macrophages, myeloid-derived suppressor cells (MDSCs), TGF-β1, and angiogenesis, along with increased functional CD8+ T cells. Mechanistically, USP22 regulated gene expression and protein stability, reducing c-Myc, PD-L1, TGF-β1, and SPARC upon Usp22 loss. Compared with KP cancer, KPU- and SPARC-knockdown KP cancers showed reduced macrophage chemotaxis and impaired basal- and TGF-β1-induced M2 polarization of RAW264.7 cells, suggesting that TGF-β1 and SPARC downregulation partially contributes to decreased M2 macrophage infiltration in KPU- cancers. Notably, Usp22 loss enhanced the efficacy of anti-PD-L1 and anti-PD-1 therapies in orthotopic and subcutaneous KP lung cancer models, respectively. USP22 and SPARC expression were also strongly correlated in human lung cancers. CONCLUSIONS: USP22 promotes progression and immune evasion in KRAS/p53-driven lung cancer. Targeting USP22 reprograms the TME, suppresses oncogenic signaling, and sensitizes tumors to ICI, establishing USP22 as a promising therapeutic target.

Animals↗

PubMed2026

Identification of candidate variants in plasma associated with early versus late disease progression under anti-PD-1 therapy in metastatic NSCLC.

BACKGROUND: Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 (anti-PD-1) antibodies, have significantly improved outcomes in patients with metastatic non-small cell lung cancer (mNSCLC). However, substantial heterogeneity exists in clinical benefit, with some patients exhibiting early progression (EP) and others late progression (LP). To date, no biomarkers of EP versus LP disease have been implemented in clinical practice. Circulating tumor DNA (ctDNA) analysis represents a minimally invasive strategy for identifying such biomarkers. In this proof-of-concept study, we evaluated the performance of the TruSight Oncology 500 ctDNA (TSO500 ctDNA) panel and explored its feasibility to identify candidate variants associated with early and late disease progression under anti-PD-1 therapy. METHODS: Baseline ctDNA from eight mNSCLC patients treated with pembrolizumab was extracted and sequenced using the TSO500 ctDNA assay, a 523-gene targeted next-generation sequencing panel. Patients were classified according to their response as LP or EP. Variant calling was performed using the DRAGEN Bio-IT platform, and variants were annotated and clinically interpreted using the Clinical Genomics Workspace (CGW; PierianDx) according to Association for Molecular Pathology (AMP)/American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. Survival outcomes were assessed using Kaplan-Meier and log-rank tests. Performance of ctDNA variants was evaluated using receiver operating characteristic (ROC) curve analysis, and multi-gene models were assessed using leave-one-out cross-validation with penalized logistic regression. RESULTS: All patients harbored detectable variants, including SNVs (100%), MNVs (87.5%), deletions (75%), and insertions (62.5%). Tier I variants were identified in 37.5% of patients, while all cases showed tier II and multiple tier III alterations. TP53 variants were associated with poorer outcomes under anti-PD-1 therapy. Individual gene alterations in TP53, ERBB3, SMC1A or LATS1 showed moderate discriminatory performance between LP and EP patients; however, combination of mutated genes improved apparent discrimination. Notably, specific two-gene combinations (SMC1A + LATS1 or ERBB3 + LATS1) showed the highest discriminatory performance between LP and EP patients in this exploratory cohort. CONCLUSIONS: This study demonstrates the feasibility and analytical performance of the TSO500 ctDNA panel and provides hypothesis-generating evidence that plasma gene variants may be useful to evaluate early versus late disease progression in patients with mNSCLC receiving immunotherapy.

TruSight Oncology 500↗

PubMed2025

Factors that increase class I MHC expression may contribute to the development of immune checkpoint inhibitor-induced diabetes.

Immune checkpoint inhibitors (ICIs) have improved survival of patients with cancer, yet they pose risks of immune-related adverse events (irAEs). ICI-induced insulin-dependent diabetes mellitus (ICI-DM) is a life-threatening and life-altering irAE. Previously, we reported a high incidence of a germline missense variant in NLRC5, a key class I transcription activator, among patients with ICI-DM compared with similarly treated patients who did not develop ICI-DM. Our purpose was to validate this finding in additional ICI-treated patients and study effects of the NLRC5 variant on expression of class I major histocompatibility complex (MHC) antigen presentation genes.We assessed the prevalence of the C>T missense variant at chr16:57 025 515 (NLRC5Pro191Leu) in germline DNA from an additional 33 patients with ICI-DM and in patients with ICI-induced colitis (n=15), ICI-induced hypothyroidism (n=19) and ICI-induced hypophysitis (n=17). The 1,000 Genomes Project was used for comparison. We assessed peripheral blood mononuclear cells from 16 individuals with or without the NLRC5 variant, studying expression of NLRC5 and select downstream target genes, before and after stimulation with interferon-γ.We validated the higher prevalence of NLRC5Pro191Leu in a non-overlapping cohort of patients with ICI-DM compared with the general population (51.5% vs 12.8%, p<0.0001). The prevalence of NLRC5Pro191Leu in ICI-induced colitis or thyroiditis patients did not significantly differ from the general population, while the prevalence in ICI-induced hypophysitis was somewhat higher (21.6%, p=0.048). We found greater increases in messenger RNA expression of NLRC5 (p=0.007), TAP1 (p=0.0002), B2M (p=0.0005), HLA-G (p=0.04), PSMB8 (p=0.03) and PSMB9 (p=0.01) in NLRC5Pro191Leu cells stimulated with interferon-γ compared with NLRC5WT cells. A similar trend was observed for HLA-A (p=0.09).We confirm the significantly higher prevalence of the NLRC5Pro191Leu variant in patients with ICI-DM relative to the general population. This abundance appears to be unique to patients who develop ICI-DM or hypophysitis on ICIs, underscoring its potential involvement in the pathogenesis of these endocrinopathies. The effects of this NLRC5 variant on class I MHC regulators suggest a mechanistic connection between the variant and development of ICI-DM. Further work is warranted to determine whether class I MHC molecules can be modulated in patients with the NLRC5Pro191Leu variant requiring ICIs.

Humans↗

PubMed2025

Population analysis and immunologic landscape of melanoma in people living with HIV.

PURPOSE: To dissect the clinical and immunological features of people living with HIV (PLWH) diagnosed with melanoma, who have consistently exhibited worse clinical outcomes than HIV-negative individuals (PLw/oH) with the same cancer. EXPERIMENTAL DESIGN: We analyzed electronic health records from 1,019 PLWH and 373,121 PLw/oH diagnosed with melanoma. Demographic and clinical characteristics were compared. Spatial immune transcriptomics (72 immune-related genes) was performed on melanoma tumor samples (n=11), followed by downstream validation using multiplex immunofluorescence (n=15 PLWH, n=14 PLw/oH). RESULTS: PLWH were diagnosed with melanoma at a younger age, had a higher representation of Hispanic and Black individuals compared to PLw/oH, and a decreased survival rate. PLWH also showed a markedly increased risk of brain metastases. PLWH experienced significant delays in initiating immune checkpoint inhibitor (ICI) therapy and had worse survival outcomes following ICI, even after balancing for demographic covariates. Spatial transcriptomics revealed a more immunosuppressive tumor microenvironment in PLWH, with upregulation of immune checkpoints (PD1, LAG3) and reduced expression of antigen presentation markers (HLA-DRB, B2M), with distinct spatial distributions in tumors and their microenvironments. Multiplex immunofluorescence confirmed an exhausted CD8+ T cell compartment in PLWH, including enrichment of PD1intLAG3- and PD1intLAG3+ subpopulations, and a significant accumulation of immunosuppressive myeloid-derived suppressor cells (CD11b+ HLA-DR- CD33+). CONCLUSIONS: Our findings suggest chronic HIV infection fosters a permissive tumor microenvironment that might undermine effective immune responses and contribute to poor clinical outcomes for PLWH with melanoma. Targeting the actionable immune pathways identified in this study could inform tailored therapeutic strategies to mitigate these disparities.

HIV↗

PubMed2025

Notch pathway defines an aggressive and immune-suppressive phenotype associated with checkpoint inhibitor resistance in pan-gastrointestinal adenocarcinomas.

The Notch pathway regulates the homeostasis and tumorigenesis of gastrointestinal epithelium. Given its roles in cancer stem cell capacity and cancer immunity, we hypothesized that Notch activation can predict poor prognosis and resistance to immune checkpoint inhibitors (ICIs) in gastrointestinal adenocarcinoma (GIAC). The mRNA expression and genomic alterations of Notch pathway were characterized in esophagus (ESAD), stomach (STAD), colon (COAD), or rectum (READ) adenocarcinomas from The Cancer Genome Atlas (TCGA) dataset. The prognostic model (mRNA-score) was constructed using the TCGA dataset (the training set) and was validated in 3 independent sets (GSE19417 [ESAD], GSE84437 [STAD], and GSE40967 [COAD]). The associations of the mRNA-score with drug sensitivity, immune cell infiltration, and immunotherapy efficacy were, respectively, analyzed using the Genomics of Drug Sensitivity in Cancer (GDSC) database, the TCGA dataset, and multiple clinical cohorts including GSE165252, PRJEB25780, IMvigor210, and CheckMate-009/010/025. Notch pathway genes exhibited conserved genomic/transcriptomic features across four GIAC subtypes. Three pan-GIAC clusters were determined by unsupervised clustering, and the cluster with higher expression of the Notch pathway genes had shorter overall survival (OS), immunosuppressive microenvironment, and higher scores of the signatures concerning angiogenesis, cell cycle, PI3K-AKT-mTOR, TGF-β, glycolysis, etc. A prognostic algorithm (mRNA-score) was constructed, which was correlated with poor OS in the training set (TCGA, P < 0.001) and three validation sets (GSE19417, P = 0.025; GSE84437, P = 0.001, GSE40967, P = 0.007). A high mRNA-score was linked with more "resting"/ "anti-inflammatory" rather than "activated"/ "pro-inflammatory" tumor-infiltrating immune cells and ICI resistance in GIACs (GSE165252, P = 0.047; PRJEB25780, P = 0.047) and other solid tumors such as urothelial carcinoma and clear cell renal cell carcinoma. Our findings demonstrate the utility of the Notch pathway in predicting prognosis and ICI resistance. Further studies are warranted to explore the efficacy of Notch inhibitors as immunotherapeutic adjuvants to overcome ICI resistance.

Humans↗

PubMed2026

Survey on the current status of novel cancer drug therapies for gynecological cancers in Japan: a nationwide survey by the Japan Society of Obstetrics and Gynecology (JSOG).

OBJECTIVE: To characterize real-world implementation of novel therapies in gynecological oncology in Japan and identify actionable gaps through a nationwide survey. METHODS: A cross-sectional questionnaire was distributed to Japan Society of Obstetrics and Gynecology-affiliated institutions. The items covered institution characteristics; use of poly (ADP-ribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors (ICIs), kinase inhibitors, and antibody-based agents; local adverse event (AE) manuals; availability of expert panels and immune-related adverse event (irAE) teams; and perceptions of educational sufficiency. RESULTS: Valid responses were obtained from 245 institutions, spanning universities, cancer centers, and general hospitals. Most institutions reported the routine use of PARP inhibitors, ICIs, kinase inhibitors, and antibody drugs. However, only 40.4% of institutions had an in-hospital irAE management team, 57.1% had an AE/irAE manual, and 31.0% and 12.2% considered prior educational opportunities sufficient for physicians and nurses/other medical staff, respectively. High-volume institutions and academic centers were significantly more likely to have medical oncology support, expert-panel access, irAE teams, manuals, and higher self-rated evidence-based management capacity. The majority favored e-learning and society-led case conferences, and 76.3% supported the development of drug therapy subspecialties in gynecologic oncology. CONCLUSION: Innovative drug modalities are widely implemented across Japanese gynecological oncology services. However, critical gaps persist in multidisciplinary irAE management, standardized manuals, and practical education. Coordinated society-led programs to expand irAE teams, streamline companion diagnostics, disseminate ready-to-use algorithms, and provide credential-targeted training may enhance safety, equity, and evidence-concordant care nationwide.

Immune Checkpoint Inhibitors↗

PubMed2026

Conserved miRNA regulators of PD-1/PD-L1 in glioblastoma and colorectal cancer.

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have transformed cancer therapy, but their efficacy remains limited in glioblastoma (GBM) and heterogeneous in colorectal cancer (CRC). MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, including immune checkpoint molecules, yet conserved regulatory miRNA networks across distinct cancers remain poorly defined. Five conserved miRNAs (miR-106a-5p, miR-106b-5p, miR-20a-5p, miR-20b-5p, miR-138-5p) fulfilled the selection criteria and were consistently dysregulated in GBM and CRC. MiR-106a-5p and miR-106b-5p were upregulated in both cancers and showed favourable prognostic associations, with higher expression correlating with improved survival. miR-20a-5p and miR-20b-5p were preferentially expressed in microsatellite-stable (MSS) CRC and correlated with favourable outcomes in both cancers, whereas miR-138-5p was downregulated in both tumours compared to normal tissue, but showed opposite survival associations, with higher levels linked to worse prognosis. Correlation analysis revealed significant inverse associations between several miRNAs and checkpoint gene expression, including moderate inverse correlations for CD274-miR-106a-5p in GBM, CD274-miR-20a-5p in CRC and PDCD1LG2-miR-20a-5p in both cancers. Pan-cancer profiling demonstrated broad and heterogeneous dysregulation, with expression absent in ovarian cancer for four of the five miRNAs. Pathway enrichment implicated the TGF-β, Hippo, FoxO, and cell cycle pathways, consistent with their known roles in tumour immune evasion. We identified a conserved set of miRNAs that are dysregulated in both GBM and CRC, correlate with survival, and display inverse relationships with PD-1/PD-L1/PD-L2 expression. These miRNAs represent candidate regulators of the PD-1/PD-L1/PD-L2 axis and potential biomarkers of tumour biology that may influence immune checkpoint signalling.

Humans↗

PubMed2026

Therapeutic melanoma vaccines: Platforms, neoantigen strategies, and emerging combination immunotherapies.

Melanoma has emerged as a major focus of cancer immunotherapy research because of its highly immunogenic nature and responsiveness to immune-based treatments. Therapeutic melanoma vaccines are designed to stimulate tumor-specific immune responses through the delivery of Tumor-Associated Antigens (TAAs), Tumor-Specific Antigens (TSAs), and personalized neoantigens. This narrative review provides an overview of current melanoma vaccine strategies, including peptide-based vaccines, dendritic cell vaccines, nucleic acid-based platforms such as mRNA, DNA, and viral vector vaccines. Recent advances in vaccine engineering and tumor genomics have accelerated the development of personalized neoantigen vaccines capable of targeting mutations unique to individual tumors. In parallel, Artificial Intelligence (AI) and Machine Learning (ML) are increasingly being incorporated into neoantigen identification pipelines to improve epitope prediction and optimize vaccine design. Combination strategies involving Immune Checkpoint Inhibitors (ICIs), particularly anti-PD-1 and anti-CTLA-4 therapies, have further enhanced interest in melanoma vaccines by helping overcome tumor-induced immune suppression and augment T-cell activation. In addition to reviewing vaccine mechanisms and emerging technologies, this manuscript examines the evolving clinical trial landscape through analysis of melanoma vaccine studies registered on ClinicalTrials.gov. Although many studies have reported encouraging safety and immunogenicity findings, challenges related to tumor heterogeneity, immune evasion, biomarker selection, and manufacturing complexity continue to limit widespread clinical implementation. Ongoing advances in computational immunology, biomaterial engineering, and precision oncology are expected to further refine melanoma vaccine development and improve therapeutic efficacy. Collectively, these innovations may help establish melanoma vaccines as an increasingly important component of future personalized cancer immunotherapy strategies.

DNA vaccines↗

PubMed2026

The clinical value of adding immune checkpoint inhibitors to radiotherapy for cancer: a systematic review and meta-analysis.

BACKGROUND: While several randomized clinical trials (RCTs) have explored the addition of immune checkpoint inhibitor (ICI) treatment for patients undergoing radiotherapy, studies systematically assessing the clinical value of such interventions are lacking. METHODS: PubMed, Embase, and Cochrane Library databases were searched for relevant RCTs of cancers that received ICIs plus radiotherapy or radiotherapy. Eligible studies were those published in English as of 14 April 2024. Two independent reviewers screened the included studies and extracted relevant data, then selected the random or fixed-effects model based on the I2 statistic. The main outcomes were hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS); Odds ratios (ORs) with 95% CIs for objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Stratified analysis was performed based on cancer type, ICI type, and the timing of ICI addition. The study was registered on PROSPERO (CRD42024551008). RESULTS: 15 RCTs with 7947 patients were included. Pooled HRs were 0.865 (95% CI, 0.730-1.000; I2 = 72.1%) for OS and 0.799 (0.677-0.922; I2 = 82.0%) for PFS in cancer patients. In cancer types, adding immunotherapy to radiotherapy significantly improved patients with non-small-cell lung cancer (OS: 0.544 [0.371-0.717]; PFS: 0.527 [0.438-0.617]) and cervical cancer (OS: 0.722 [0.578-0.867] and PFS: 0.754 [95%CI, 0.621-0.887]). Regarding the ICIs schedule, adjuvant ICI therapy with pooled HRs was 0.742 (0.649-0.834) for OS and 0.638 (0.579-0.697) for PFS. In addition, the pooled ORs for the incidence of grade 3 or higher treatment-related and immune-related adverse events were 1.227 (1.059-1.421; I2 = 71.9%) and 2.217 (1.743-2.821; I2 = 74.0%), respectively. CONCLUSION: Adding immunotherapy to radiotherapy can provide significant clinical benefits for patients with NSCLC and cervical cancer, and the addition of these ICIs in the adjuvant stage is supported.

Humans↗

PubMed2025

Effect of extracellular vesicles in remodeling the tumor microenvironment by DNMT1 downregulation for enhanced cancer immunotherapy.

BACKGROUND: The efficacy of immunotherapy is often hindered by the suppression of immune responses via the tumor microenvironment (TME). The presence of cancer cells forces other proximal non-cancerous cells to support tumor growth and persistence. A clear example of this cancerous-to-non-cancerous communication is represented by the accumulation of myeloid-derived suppressor cells (MDSCs) within the TME. Several studies have convergently shown that the overexpression of DNA-methyl-transferase-1 (DNMT1) in these cells results in protection from necroptosis and enhanced accumulation in vivo. Conversely, targeting DNMT1 through hypo-methylating agents has shown promising therapeutic potential by not only reducing the levels of MDSCs but also enhancing cancer immunogenicity and the efficacy of immune checkpoint inhibitors (ICI). METHODS: Murine 4T1 (triple-negative breast cancer (TNBC)) and CT26 (colon carcinoma) cell lines were cultured under standard conditions and used to generate tumor models in BALB/c mice. An oncolytic adenovirus expressing a DNMT1-targeting short hairpin RNA (OAd.shDNMT1) was engineered and validated for DNMT1 knockdown and genome-wide methylation reduction. Small extracellular vesicles (sEVs) were isolated from virus-infected cancer cells and characterized for RNA content and uptake by MDSCs. MDSC differentiation and suppressive function were assessed in vitro using flow cytometry and co-culture assays with murine splenocytes. In vivo, tumor-bearing mice received intratumoral OAd.shDNMT1, systemic decitabine, or immune checkpoint inhibitors (anti-Programmed cell Death protein-1), and tumor growth, immune infiltration, and systemic MDSC levels were evaluated. RESULTS: In this study, we report that, by using virally infected TNBC murine cells as a source for shDNMT1-loaded sEVs, OAd.shDNMT1 successfully reduced MDSC levels in vitro and in vivo. Furthermore, the co-administration with ICI resulted in a significant tumor growth reduction in mice bearing poorly immunogenic TNBC 4T1 cells. Also, our treatment promoted antitumor immunity, prolonged survival, and complete tumor eradication in modestly immunogenic colon CT26 cancer cells. CONCLUSION: This multifaceted strategy, based on OV-mediated immune stimulation and reduction of MDSC levels via sEVs, may improve clinical outcomes and the success of immuno-based regimens for patients facing MDSC-rich and highly aggressive cancer subtypes.

Animals↗

PubMed2026

Beyond the "cold" barrier: Redefining the clinical paradigm of immune checkpoint inhibitor therapy in ovarian cancer.

Ovarian cancer remains an immunologically "cold" tumor, with early all-comer immune checkpoint inhibitor (ICI) trials largely negative despite underlying immunogenicity. This review takes a clinician-centric, stage-specific view linking regimen choice, treatment line, and tumor-immune context to observed outcomes. In the neoadjuvant and first-line settings, unselected ICI combinations with chemotherapy and anti-angiogenic agents failed to improve progression-free survival, whereas adding a poly (ADP-ribose) polymerase (PARP) inhibitor to ICI maintenance yielded modest gains in biomarker-enriched cohorts. In recurrent disease, single-agent ICIs produced objective response rates of 8-15%, and most randomized combinations were negative. The phase III KEYNOTE-B96 trial in platinum-resistant disease demonstrated a progression-free survival benefit in the intention-to-treat population and an overall survival benefit in tumors with programmed death ligand 1 (PD-L1) combined positive score ≥ 1 when pembrolizumab was paired with weekly paclitaxel with or without bevacizumab, underscoring the value of an immunomodulatory chemotherapy backbone in earlier lines. Ovarian clear cell carcinoma emerges as an immunotherapy-sensitive, chemo-resistant subtype that warrants dedicated stratification. We explain why single-analyte biomarkers-PD-L1, tumor mutational burden, homologous recombination deficiency/BRCA1/2-have not reliably enriched benefit and outline a multidimensional approach integrating genomic scars (e.g., mutational signature 3), immune functional state (Immunoscore, CD8⁺ tumor-infiltrating lymphocyte density and CD8⁺: regulatory T-cell ratio), and spatial architecture (inflamed, excluded, desert phenotypes). This framework aims to move beyond the all-comer era toward context-informed precision immunotherapy in ovarian cancer.

Humans↗

PubMed2026

Distinct immune landscapes characterize highly versus minimally invasive brain metastases.

Brain metastases (BrMs) occur in approximately 30% of cancer patients, causing nearly one-fifth of cancer deaths. While immune checkpoint inhibitors (ICIs) benefit some BrM patients, responses remain highly variable. This variability partly reflects distinct histopathological growth patterns that include minimally invasive (MI) and highly invasive (HI) brain BrMs. Here we show that MI BrMs exhibit robust immune infiltration, whereas HI lesions are immunosuppressed. However, histological differentiation between MI and HI can be challenging because of subjective margin assessment. Here, using highly multiplexed spatial proteomics on 119 tumor sections from 46 patients with BrMs, we identify CHI3L1 as a key mediator of the immunosuppressive microenvironment in HI BrMs. In preclinical models, genetic deletion of CHI3L1 converts immune-cold metastases into lymphocyte-rich, ICI-responsive lesions infiltrated by granzyme B+ CD8+ T cells. In BrM patients treated with ICI, immunohistochemical quantification of CHI3L1 expression was a stronger predictor of ICI response than traditional MI/HI classification. Thus, CHI3L1 represents a promising biomarker and therapeutic target for BrMs.

Humans↗

PubMed2026

The Addition of Concurrent Immune Checkpoint Inhibitors for Chemoradiotherapy With Consolidative Immune Checkpoint Inhibitors in Unresectable Cancers: A Systematic Review and Meta-Analysis.

Following the success of chemoradiotherapy (CRT) combined with consolidative immune checkpoint inhibitors (ICIs) in locally advanced tumors, over 30 ongoing randomized controlled trials (RCTs) are investigating the potential benefits of adding concurrent ICIs. To investigate the differences in efficacy and safety between adding and not adding concurrent ICIs to CRT followed by consolidative ICIs, a literature search was conducted in PubMed, Embase, and the Cochrane Library, incorporating RCTs comparing CRT combined with consolidative ICIs versus CRT alone, or CRT with both concurrent and consolidative ICIs versus CRT alone. The primary outcomes were overall survival (OS) and progression-free survival (PFS). To reduce potential bias, an additional mirror-design analysis was performed through network meta-analysis. A total of 13 RCTs comprising 6868 patients and 14 cohort studies comprising 4724 patients were included. While patients treated with CRT and consolidative ICIs demonstrated significantly superior OS and PFS to patients treated with CRT alone in RCTs (HR of OS, 0.743, 95% CI, 0.654-0.843; HR of PFS, 0.674, 95% CI, 0.577-0.786), CRT and concurrent-plus-consolidative ICIs did not improve OS and PFS compared with CRT alone (HR of OS, 0.942, 95% CI, 0.782-1.134; HR of PFS, 0.880, 95% CI, 0.752-1.030). Significant differences were detected in OS (p = 0.038) and PFS (p = 0.017) between CRT combined with consolidative ICIs treatment versus CRT combined with concurrent and consolidative ICIs treatment from RCTs. In conclusion, adding concurrent ICIs may dampen the survival benefits of CRT combined with consolidative ICIs. This evidence informs future RCT design strategies.

Humans↗