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PubMed2026

Recent advances in immunotherapy for breast cancer: An updated review.

Immunotherapy has revolutionized the treatment landscape of breast cancer, particularly for triple-negative breast cancer (TNBC), yet primary and acquired resistance remain formidable obstacles limiting durable clinical benefit. This review provides a comprehensive update on recent advances in breast cancer immunotherapy, with a focused emphasis on the molecular and cellular mechanisms driving treatment resistance and emerging strategies to overcome them. We dissect tumor-intrinsic resistance pathways, including loss of tumor antigens, defects in antigen processing and presentation machinery, insensitivity to interferon-γ signaling, metabolic reprogramming, and epigenetic dysregulation. Tumor-extrinsic mechanisms, such as infiltration of immunosuppressive cells, abnormal angiogenesis, extracellular matrix remodeling, and FGF/FGFR genomic amplification, are highlighted as key barriers to effective immune checkpoint blockade. Emerging evidence implicates novel resistance mediators, including the DUSP22-LGALS1 axis, THSD4-driven T cell exclusion, and the MTDH-SND1 complex impairing antigen presentation, etc. We critically evaluate current strategies to surmount resistance, encompassing combination regimens with chemotherapy, targeted therapies, radiotherapy, and novel immunomodulators. The review also addresses challenges in managing immune-related adverse events, controversies surrounding patient selection biomarkers, and the urgent need for optimized efficacy evaluation systems beyond RECIST criteria. Finally, we discuss future directions, including novel immune checkpoints, microbiome modulation, artificial intelligence-assisted decision-making, and innovative trial designs. By integrating mechanistic insights with clinical evidence, this review provides a framework for understanding and overcoming immunotherapy resistance, advancing the paradigm from "effective" to "precise" immuno-oncology in breast cancer.

Humans↗

PubMed2025

Digital Immunophenotyping of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Subtypes With Specific Tumor-Immune Microenvironment Features.

Atypical carcinoids (ACs) and large cell neuroendocrine carcinomas (LCNECs) are defined by the WHO as intermediate- and high-grade lung neuroendocrine neoplasms, respectively, based on morphological criteria; however, treatment strategies remain debated. Given the emerging role of the tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) in cancer prognosis and therapy response, this study aimed to characterize the immune landscape of ACs and LCNECs comprehensively. Immunohistochemistry for T-cell markers (CD3, CD8), immune checkpoints (PD-1, PD-L1), HLA molecules (HLA-DR, HLA-I), and fibroblasts (α-SMA) was performed on a re-evaluated cohort of 56 ACs and 104 LCNECs. Digital image analysis quantified intra-tumor (iTILs) and stromal (sTILs) CD3 and CD8 TILs in the whole slide and in specific tumor regions (invasive margin [IM] and central tumor [CT]). LCNECs exhibited significantly higher stromal T-cell infiltration, immune checkpoint expression, and HLA compared to ACs (p < 0.001), while α-SMA was more prominent in ACs. No ACs showed PD-L1 tumor expression. Digital quantification confirmed greater iTILs and sTILs in LCNECs across all regions, with moderate concordance to manual counts. Interestingly, TIL parameters were higher at the IM than in the CT (p < 0.001). Using Boruta feature selection algorithm, Principal Component Analysis and Hierarchical Clustering, three patient clusters were identified: Cluster 1 (mainly ACs, low TILs, favorable prognosis), Cluster 2 (mixed histology, intermediate TILs, moderate prognosis), and Cluster 3 (mostly LCNECs, high TILs, poor prognosis), with distinct TME marker profiles. PD-L1 tumor expression was strongly linked to Cluster 3. These findings suggest that ACs and LCNECs may be stratified into three distinct immune clusters, highlighting the heterogeneity of their tumor microenvironment and providing a rationale for further translational studies.

Humans↗

PubMed2026

A machine learning-derived intratumoral heterogeneity-related signature predicts the prognosis for and therapeutic response in patients with skin cutaneous melanoma.

BACKGROUND: Reliable biomarkers for predicting prognosis and therapeutic response in skin cutaneous melanoma (SKCM) remain limited. This study aimed to develop an intratumoral heterogeneity (ITH)-related prognostic signature for SKCM using integrative machine learning. METHODS: RNA sequencing (RNA-seq) data from 472 SKCM patients in The Cancer Genome Atlas (TCGA) and 214 patients in the GSE65904 cohort were analyzed. ITH scores were calculated using the DEPTH2 algorithm. Differentially expressed genes (DEGs) were identified between high- and low-ITH groups [|log2fold change (FC)| ≥1, false discovery rate (FDR) <0.05]. Based on 38 prognostic DEGs identified by univariate Cox regression, we employed an integrative framework of 101 machine learning algorithm combinations to construct prognostic models in the TCGA training cohort. The model with the highest average concordance index (C-index) was validated in the GSE65904 cohort and selected as the prognostic ITH-related signature (PIRS). Associations of the PIRS risk score with tumor mutational burden (TMB), immune cell infiltration, immune checkpoint gene expression, and drug sensitivity were systematically evaluated. Model performance was assessed using receiver operating characteristic (ROC) curves and Cox regression analyses. RESULTS: A 38-gene PIRS was constructed using the plsRcox algorithm. Patients with high PIRS risk scores exhibited significantly poorer overall survival (OS) in both the TCGA and Gene Expression Omnibus (GEO) cohorts. The PIRS was identified as an independent prognostic factor, with area under the curve (AUC) values of 0.779, 0.734, and 0.756 for 1-, 3-, and 5-year survival, respectively. High-risk samples displayed significantly lower TMB (P<0.05), reduced immune and stromal cell infiltration (P<0.001), downregulated immune function, and decreased expression of immune checkpoint genes. Additionally, high- and low-PIRS risk score groups exhibited distinct sensitivity patterns to different classes of targeted agents. CONCLUSIONS: The machine learning-derived PIRS robustly predicts prognosis in SKCM patients. Its clinical application is promising for optimizing patient risk stratification and treatment decisions, though further prospective validation is warranted.

Skin cutaneous melanoma (SKCM)↗

PubMed2026

Pan-cancer Bioinformatics Analysis Combined with Colon Cancer Experimental Validation: A Study on TMED3 as a Diagnostic and Prognostic Biomarker.

Transmembrane Emp24 Protein Transport Domain 3 (TMED3), a member of the p24 protein family, has been implicated in tumor proliferation, invasion, and migration. This study aimed to evaluate the expression patterns, prognostic significance, immune associations, and potential biological functions of TMED3 across multiple cancer types using pan-cancer bioinformatics analysis combined with immunohistochemical (IHC) validation in colon cancer. Multiomics datasets from The Cancer Genome Atlas, Genotype-Tissue Expression, UALCAN, Human Protein Atlas, and cBioPortal databases were analyzed to investigate TMED3 expression and genetic alterations in pan-cancer. Immunohistochemistry was performed to evaluate TMED3 protein expression in colon cancer tissues. Kaplan-Meier survival analysis and Cox regression analysis were used to assess the prognostic value of TMED3. Spearman correlation analysis was conducted to evaluate the associations of TMED3 with tumor mutational burden, microsatellite instability (MSI), immune cell infiltration, and immune checkpoints. Gene Set Enrichment Analysis was performed to investigate potential biological pathways associated with TMED3 in colon cancer. TMED3 expression was elevated in most tumor types and was associated with unfavorable overall survival and disease-specific survival in adrenocortical carcinoma, colon adenocarcinoma, and uveal melanoma. The greatest frequency of TMED3 genetic alterations was identified in mesothelioma, with amplification representing the predominant alteration type. In addition, TMED3 expression showed significant correlations with tumor mutational burden and microsatellite instability in kidney renal clear cell carcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. TMED3 expression was also associated with immune infiltration and immune checkpoint expression in several tumors. IHC analysis demonstrated increased TMED3 expression in colon cancer tissues compared with normal colon tissues and showed an association with T stage. Functional enrichment analysis identified pathways related to ribosome, antigen processing and presentation, oxidative phosphorylation, and pentose phosphate. These findings indicate that TMED3 may represent a promising biomarker for the diagnosis and prognostic evaluation of colon cancer as well as other tumor types.

Humans↗

PubMed2025

Modulation of the tumor microenvironment by the ubiquitin-proteasome system in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with the tumor microenvironment (TME) playing a pivotal role in its progression and therapeutic resistance. The ubiquitin-proteasome system (UPS), a central regulator of intracellular protein degradation, is increasingly recognized for its involvement in cancer pathogenesis, though its specific role in modulating the CRC TME remains to be fully elucidated. This review aims to systematically summarize current evidence on how the UPS influences the immunosuppressive network within the CRC TME and to evaluate its potential as a therapeutic target. METHODS: We conducted a comprehensive literature search in PubMed, Web of Science, and Scopus databases for original research articles and reviews published between January 2010 and August 2025, using keywords including "ubiquitin-proteasome system," "colorectal cancer," "tumor microenvironment,""immune escape,"and "targeted therapy." Studies were selected based on their relevance to UPS-mediated regulatory mechanisms in CRC TME remodeling, immune cell function, and treatment response. RESULTS: Our analysis of preclinical and clinical evidence reveals that the UPS critically regulates immune evasion in CRC through multiple mechanisms: (1) USP14 stabilizes indoleamine 2,3-dioxygenase 1 (IDO1), enhancing tryptophan catabolism and kynurenine accumulation, which suppresses T-cell activity; (2) E3 ligases including SPOP, C-Cbl, KLHL22, and FBW7 modulate PD-L1/PD-1 protein stability via ubiquitination, thereby influencing immune checkpoint signaling; and (3) ZFP91 facilitates K63-linked ubiquitination of PP2Ac, impairing mTORC1-mediated glycolysis in T cells and reinforcing regulatory T-cell immunosuppression. Additionally, the UPS intersects with key oncogenic pathways such as Wnt/β-catenin, NF-κB, and p53, further shaping the immunosuppressive landscape of CRC. CONCLUSIONS: Targeting the UPS represents a promising strategy to reverse immunosuppression and overcome therapy resistance in CRC. The primary advantage of this approach lies in its ability to simultaneously disrupt multiple immunosuppressive pathways within the TME, offering a potential solution to the limitations of single-target therapies. Current approaches include proteasome inhibitors, E3 ligase modulators, and deubiquitinating enzyme inhibitors, with combination regimens-such as UPS inhibitors with immune checkpoint blockade-showing synergistic efficacy in preclinical models. Future efforts should focus on enhancing the selectivity of UPS-targeting agents, minimizing off-target effects, and integrating genomic profiling to guide personalized treatment. While current evidence strongly supports the therapeutic potential of UPS targeting, its establishment as a reliable alternative therapy in the clinic will depend on overcoming these challenges and validating efficacy in human trials. This review underscores the UPS as a central regulator of the CRC TME and provides a rational basis for novel therapeutic development.

Humans↗

PubMed2026

Rationale and Study Design of the GUIDANCE trial: A Multicenter Phase II Trial of Maintenance Durvalumab and Olaparib After Standard Fist Line Treatment (Carboplatin/Cisplatin, Etoposide, and Durvalumab) in HRD Positive Extensive Disease (ED) Small-cell Lung Cancer (SCLC) (AIO-TRK-0124/ass).

BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis and limited therapeutic progress over recent decades. Although PD-L1 inhibitors have modestly improved survival, responses are not durable. There are no predictive biomarkers that would allow for a personalized treatment strategy. Targeting DNA damage repair deficiencies represents a promising treatment strategy in various solid tumors. Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib have demonstrated efficacy in homologous recombination deficiency (HRD)-positive tumors, and preclinical data suggest synergistic activity with immune checkpoint blockade. METHODS: GUIDANCE is a biomarker-driven, multicenter, single-arm, open-label phase II trial evaluating maintenance therapy with durvalumab and olaparib in patients with advanced or metastatic SCLC without progression after first-line therapy with platinum, etoposide and durvalumab. Patients are prospectively selected for HRD based on homologous recombination repair gene alterations and/or a genomic instability score. Following central prescreening, 29 patients will be enrolled. Patients receive durvalumab (1500 mg every 4 weeks) and olaparib (300 mg twice daily) until progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by RECIST 1.1. Secondary endpoints are overall survival, safety and tolerability. Exploratory analyses include circulating tumor DNA (ctDNA) monitoring of individual TP53 mutations, assessment of SLFN11 expression, and characterization of immune cell composition via multiplex immunohistochemistry. DISCUSSION: This trial investigates a chemotherapy-free, genomically stratified maintenance strategy targeting both DNA damage repair deficiency and immune evasion in SCLC. By integrating HRD-based patient selection with concurrent PARP and immune checkpoint inhibition, GUIDANCE aims to establish a more individualized therapeutic approach and to generate a signal for further evaluation in biomarker-defined patient populations. Trial registration number EuraCT 2024-512373-27-00.

DNA-damage repair↗

PubMed2026

Integrative analysis identifies a glycosylation-related lncRNA signature associated with prognosis in kidney renal clear cell carcinoma.

BACKGROUND: Glycosylation and long non-coding RNAs (lncRNAs) play critical roles in tumor progression. However, the prognostic significance of glycosylation-related lncRNAs (GRLncs) in kidney renal clear cell carcinoma (KIRC) remains largely unclear. This study aimed to identify prognostic GRLncs and construct a predictive model for KIRC prognosis. METHODS: Transcriptomic and clinical data of KIRC patients were analyzed to identify GRLncs associated with overall survival (OS). A prognostic model was constructed based on selected GRLncs, and its predictive performance was evaluated using Kaplan-Meier (KM) survival analysis, receiver operating characteristic (ROC) curves, and univariate and multivariate Cox regression analyses. Patients were stratified into high- and low-risk groups according to the median risk score, and internal validation was performed using training and testing cohorts to assess the stability of the model. Tumor microenvironment characteristics, immune checkpoint expression, immunotherapy response, and drug sensitivity were further analyzed. In addition, the expression of three signature lncRNAs was validated by real-time quantitative polymerase chain reaction (RT-qPCR) in 10 paired KIRC tumor and adjacent normal tissues. Functional roles of selected lncRNAs were investigated using antisense oligonucleotides (ASOs)-mediated knockdown in KIRC cell lines, followed by Cell Counting Kit 8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, colony formation, and migration assays. RESULTS: Five GRLncs (AC093278.2, EPB41L4A-DT, DLGAP1-AS2, AC084876.1, and AC005261.3) were identified and used to construct a prognostic model. AC093278.2 and EPB41L4A-DT were protective factors, whereas DLGAP1-AS2, AC084876.1, and AC005261.3 were risk factors. KM analysis on GRLncs-based risk score stratification revealed patients in the high-risk group had significantly poorer OS than those in the low-risk group. ROC analysis and Cox regression demonstrated that the GRLnc-based risk score served as an independent predictor of KIRC prognosis and exhibited favorable predictive performance compared with conventional clinical variables. High- and low-risk groups also exhibited distinct immune microenvironment characteristics, immune checkpoint expression patterns, and predicted drug sensitivities. RT-qPCR detected significant downregulation of protective factor-EPB41L4A-DT in KIRC tissues, while risk factors-DLGAP1-AS2 and AC084876.1 showed expression trends consistent with their predicted risk attributes. Functional experiments further revealed that knockdown of DLGAP1-AS2 and AC084876.1 suppressed proliferation and migration of KIRC cells, whereas knockdown of EPB41L4A-DT promoted these processes, supporting the biological relevance of these three signature lncRNAs. CONCLUSIONS: This study establishes a novel prognostic model based on five GRLncs that showed promising performance in The Cancer Genome Atlas (TCGA)-based analyses of KIRC. The combined clinical expression analysis and functional validation of three constituent GRLncs (DLGAP1-AS2, EPB41L4A-DT, and AC084876.1) supports the biological plausibility of the model and suggest that GRLncs may serve as potential prognostic biomarkers and therapeutic targets for KIRC.

Kidney renal clear cell carcinoma (KIRC)↗

PubMed2025

HMGA2 links morphological evolution and microenvironment dynamics to systemic therapy response in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) exhibits significant heterogeneity due to morphological changes and tumor microenvironment dynamics, influencing systemic therapy responses. While the role of high-mobility group AT-hook 2 (HMGA2) in tumor progression has been implicated in other cancers, its significance in ccRCC remains unclear. This study investigates the role of HMGA2 in these processes and its clinical impact. METHODS: Spatial transcriptomics (ST) was performed on primary ccRCC samples to investigate expression trajectories associated with HMGA2 expression and morphological evolution. In metastatic ccRCC cohorts treated with systemic therapy, immunohistochemistry and bulk RNA sequencing data were analyzed to evaluate molecular and clinical features in relation to HMGA2. Single-cell RNA sequencing (scRNA-seq) data were used to explore immune cell populations and their interactions. Based on these findings, multiplex immunohistochemistry (mIHC) assessed spatial distribution, cell-cell interactions, and pathological responses of key immune populations. RESULTS: HMGA2 expression was associated with aggressive morphological patterns, such as solid sheets and rhabdoid/sarcomatoid. ST revealed a progressive increase in HMGA2 expression along the morphological trajectory, marked by a shift from clear to eosinophilic cytoplasm, with eccentric nuclei and prominent nucleoli, and loss of vascular architecture. HMGA2-high tumors exhibited aggressive phenotypes driven by cell cycle, epithelial-mesenchymal transition, and inflammatory signaling pathways. Clinically, patients with high HMGA2 had worse progression-free survival but responded better to immune checkpoint inhibitor combination (Combo-ICI) therapy than to tyrosine kinase inhibitor monotherapy. To assess the immune landscape, scRNA-seq data revealed that HMGA2-high tumors were enriched with progenitor exhausted CD8+ T cells (Tpex), along with increased frequencies of conventional dendritic cell type 1 (cDC1) and inflammatory cDC type 2, which were found to interact with Tpex via ICAM-1. mIHC confirmed that Tpex were enriched among Combo-ICI responders in HMGA2-high tumors, with higher densities and closer proximity to ICAM-1+ cDC1. CONCLUSIONS: These findings suggest that dynamic HMGA2 expression contributes to morphological evolution and modulates immune responses through enhanced Tpex-cDCs engagement, serving as a potential marker for systemic therapy response in ccRCC. However, additional experimental studies are required to validate these mechanisms.

Humans↗

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↗

PubMed2026

Oral melanoma in the immunotherapy era: Immune evasion, resistance, and therapeutic opportunities.

Oral melanoma (OM) is a rare and highly aggressive mucosal malignancy associated with poor survival and limited evidence to guide immunotherapy. This narrative review synthesizes current knowledge on OM immunobiology and its therapeutic implications. OM differs from cutaneous melanoma in its origin in sun-protected sites, genomic architecture, and heterogeneous immune microenvironments, features that can contribute to attenuated responses to immune checkpoint inhibitors. Anti-PD-1-based therapy has demonstrated clinical activity in mucosal melanoma, and selected OM cases have shown meaningful responses, including in multimodal and perioperative settings. However, OM-specific prospective data remain sparse, and the available evidence is largely derived from pooled mucosal melanoma cohorts or case reports. Emerging combination strategies, such as antiangiogenic agents, radiotherapy, and perioperative immunotherapy, remain insufficiently validated. This review critically reappraises the available evidence, identifies key knowledge gaps, and outlines future directions for biomarker-driven, OM-specific translational research.

Humans↗

PubMed2026

Novel immunotherapeutic strategies for colorectal cancer treatment: Advances, challenges, and future directions.

Immunotherapy has reshaped the treatment landscape of colorectal cancer (CRC), with the clearest and most durable benefit established in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) disease. However, framing CRC immunotherapy simply as "MSI-H responsive versus microsatellite stable (MSS) resistant" is no longer sufficient. Recent studies indicate that a subset of proficient mismatch repair (pMMR) colon cancers, particularly in the neoadjuvant setting, can mount clinically meaningful responses to immune checkpoint blockade, suggesting that disease stage, local immune organization, and treatment timing critically influence immunotherapy sensitivity. In parallel, emerging evidence has expanded the relevant immune landscape beyond the tumor bed itself, showing that spatially organized stromal and adipose niches can actively divert tumor-reactive lymphocytes and promote immune escape. These advances shift the central challenge in CRC immunotherapy from simply identifying new agents to defining when and in whom immune resistance is reversible, and which biological bottlenecks-such as vascular dysfunction, myeloid suppression, and spatial immune exclusion-must be overcome. In this context, alternative checkpoint inhibitors, bispecific antibodies, cellular therapies, vaccines, nanotechnology-enabled platforms, and microbiome-targeted approaches remain important, but their translational maturity and evidentiary support differ substantially. Biomarker development is likewise evolving from static genomic classification toward dynamic and mechanism-informed stratification incorporating circulating tumor DNA (ctDNA), chromosomal instability, immune architecture, and treatment-induced response trajectories. This review synthesizes recent advances in CRC immunotherapy while emphasizing evidence hierarchy, biomarker-guided patient selection, and the mechanistic basis of combination strategies. We argue that the next phase of CRC immunotherapy will depend less on the indiscriminate addition of novel agents and more on the rational deployment of immunotherapy across molecularly, spatially, and temporally defined disease states.

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

Safety, Pharmacokinetics, and Pharmacodynamics of Single-Dose Programmed Cell Death Protein 1 Inhibitor, Budigalimab, in People With HIV-1 With Antiretroviral Therapy-Suppressed Viral Load.

BACKGROUND: Blockade of inhibitory immune checkpoint receptor programmed cell death protein 1 (PD-1) on target immune cells is associated with improved HIV-specific immune function and activation of latent HIV. This randomized, placebo-controlled, Phase 1b study assessed low doses of investigational anti-PD-1 monoclonal antibody, budigalimab, for safety, tolerability, pharmacokinetics, and pharmacodynamics in people with HIV (PWH) on antiretroviral therapy. METHODS: Participants received single doses of budigalimab 10 mg subcutaneous (SC), 20 mg SC, 10 mg intravenous (IV), or placebo (n = 8 per arm) and were followed for 24 weeks. RESULTS: Of 32 randomized participants, 22 reported adverse event(s) (AE); most (n = 19) were grade ≤2 and no grade ≥4 AE or treatment-related serious AE. Two participants reported a non-treatment-related grade 3 AE (placebo, n = 1 pneumonia; 10 mg IV, n = 1 elevated aspartate aminotransferase). One reversible immune-related AE (grade 2 lichenoid keratosis) was reported (20 mg SC). Geometric mean maximum serum concentrations were 0.37, 1.57, and 3.2 µg/mL with 10 mg SC, 20 mg SC, and 10 mg IV, respectively. Drug exposure with 20 versus 10 mg SC dosing was more than dose proportional and less variable. Subcutaneous bioavailability was approximately 53%-62%. The PD-1 receptor saturation was ≥95% in most participants (median duration: 20 mg SC, 42 days; 10 mg SC, 14 days; 10 mg IV, 35 days). CONCLUSIONS: Findings suggest an acceptable safety profile for single-dose budigalimab in PWH, with a favorable pharmacokinetic profile for 20 mg SC and 10 mg IV. Further evaluation as a potential component of an HIV treatment is underway.

Humans↗

PubMed2024

Fecal microbiota transplantation improves anti-PD-1 inhibitor efficacy in unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor.

The gut microbiome significantly influences immune responses and the efficacy of immune checkpoint inhibitors. We conducted a clinical trial (NCT04264975) combining an anti-programmed death-1 (PD-1) inhibitor with fecal microbiota transplantation (FMT) from anti-PD-1 responder in 13 patients with anti-PD-1-refractory advanced solid cancers. FMT induced sustained microbiota changes and clinical benefits in 6 of 13 patients, with 1 partial response and 5 stable diseases, achieving an objective response rate of 7.7% and a disease control rate of 46.2%. The clinical response correlates with increased cytotoxic T cells and immune cytokines in blood and tumors. We isolated Prevotella merdae Immunoactis from a responder to FMT, which stimulates T cell activity and suppresses tumor growth in mice by enhancing cytotoxic T cell infiltration. Additionally, we found Lactobacillus salivarius and Bacteroides plebeius may inhibit anti-tumor immunity. Our findings suggest that FMT with beneficial microbiota can overcome resistance to anti-PD-1 inhibitors in advanced solid cancers, especially gastrointestinal cancers.

Adult↗

PubMed2025

Proposal of real-world solutions for the implementation of predictive biomarker testing in patients with operable non-small cell lung cancer.

The implementation of biomarker testing for targeted therapies and immune checkpoint inhibitors is a cornerstone in the management of metastatic and locally advanced non-small cell lung cancer (NSCLC), playing a pivotal role in guiding treatment decisions and patient care. The emergence of precision medicine in the realm of operable NSCLC has been marked by the recent approvals of osimertinib, atezolizumab, nivolumab, pembrolizumab and alectinib for early-stage disease, signifying a shift towards more tailored therapeutic strategies. Concurrently, the landscape of this disease is rapidly evolving, with several further pending approvals and numerous clinical trials in progress. To harness the benefits of these innovative neo-adjuvant and adjuvant therapies, the integration of predictive biomarker testing into standard clinical protocols is imperative for patients with operable NSCLC. A multidisciplinary international consortium has identified three primary obstacles impeding the effective testing of patients with operable NSCLC. These challenges encompass the limited number of test requests by physicians, the inadequacy of tissue samples for comprehensive testing, and the prevalence of cost-reduction measures leading to suboptimal testing practices. This review delineates the aforementioned challenges and proposed solutions, and strategic recommendations aimed at enhancing the testing process. By addressing these issues, we strive to optimize patient outcomes in operable NSCLC, ensuring that individuals receive the most appropriate and effective care based on their unique disease profile.

Humans↗

PubMed2026

Amivantamab in Recurrent/Metastatic Head and Neck Squamous Cell Cancer After Checkpoint Inhibitor and Chemotherapy: Pivotal Results From the Phase Ib/II OrigAMI-4 Study.

Single-agent paclitaxel or cetuximab after immune checkpoint inhibitor (ICI) and chemotherapy demonstrated objective response rates (ORRs) of 21%-24% in recurrent/metastatic (R/M) head/neck squamous cell cancer (HNSCC). Epidermal growth factor receptor (EGFR) and MET are overexpressed in R/M HNSCC. Amivantamab, an EGFR-MET bispecific antibody, may be a rational treatment. Cohort 1 of OrigAMI-4 (ClinicalTrials.gov identifier: NCT06385080) evaluated subcutaneous amivantamab administered every 3 weeks in participants with non-human papillomavirus R/M HNSCC after PD-(L)1 inhibitor and platinum-based chemotherapy. Prior anti-EGFR therapy and p16-positive oropharyngeal cancer were exclusionary. The primary end point was RECIST v1.1 ORR. Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. In 102 participants, blinded independent central review‑assessed ORR was 42% (95% CI, 32 to 52); the complete response rate was 15%. Median DoR was not reached (NR; 95% CI, 6.9 to NR); 56% of responses lasted ≥6 months. Investigator-assessed ORR was 47% (95% CI, 37 to 57). At a median follow-up of 11.8 months (range, 1.1-21.9), median PFS and OS were 6.8 months (95% CI, 5.2 to 8.3) and 12.5 months (95% CI, 10.2 to 16.8), respectively. Adverse events were consistent with previous experience with no new safety signals. Treatment-related discontinuations were low (8%). Amivantamab demonstrated greater antitumor activity in participants previously exposed to ICI and chemotherapy than has been reported for paclitaxel or cetuximab.

Humans↗

PubMed2026

High dietary fiber is associated with improved outcomes in patients with melanoma and sarcoma treated with immunotherapy regardless of gut microbiome dysbiosis and social vulnerability.

BACKGROUND: Social vulnerability, dietary fiber, and the gut microbiome have been individually implicated in clinical outcomes for melanoma and sarcoma patients. This study hypothesized that increasing social vulnerability is associated with insufficient dietary fiber intake and negatively associated with microbiome composition and clinical outcomes. METHODS: Clinicopathologic data, baseline fiber intake, and gut microbiome profiles were assessed in 153 patients with melanoma or sarcoma treated with immune checkpoint blockade (ICB) and prospectively followed. Patients' social vulnerability index (SVI) and fiber intake were evaluated for associations with microbiome composition, treatment response, and overall survival (OS). RESULTS: SVI percentile was 0.4 (interquartile ratio [IQR], 0.2-0.7), and median dietary fiber intake was 17 (IQR, 15-20) g/day. SVI was inversely correlated with dietary fiber intake (r, -0.18, p = .0398). Gut microbiome analyses revealed community and compositional differences by SVI, including inverse associations with α-diversity and the relative abundance of favorable bacteria such as Bifidobacterium longum (p < .001), contrasting the positive associations observed between fiber and these microbial markers. Increased dietary fiber intake was associated with measurable response to ICB. A difference in OS was not observed in more socially vulnerable patients (SVI, not reached vs. 81.7 months), however, a survival advantage was evident with higher dietary fiber intake (not reached, 58.9 months). CONCLUSIONS: Increased social vulnerability was associated with a less favorable gut microbiome composition but not worse OS among melanoma and sarcoma patients treated with ICB. Consistent with prior findings, high dietary fiber intake emerged as a potentially modifiable pathway to improve outcomes in patients initiating ICB, particularly those with increased SVI.

Humans↗

PubMed2026

Response-adapted surgical de-escalation following neoadjuvant immunotherapy in resectable mucosal HNSCC A systematic review and meta-analysis.

INTRODUCTION: Recent encouraging outcomes with neoadjuvant immune checkpoint inhibitors (ICIs) in mucosal head and neck squamous cell carcinoma (HNSCC) have generated interest in surgical de-escalation. However, the oncologic safety of response-adapted surgery (RAS) and its ability to achieve survival outcomes comparable to baseline-planned surgery (BPS) remain uncertain. METHODS: A systematic search of the PubMed, EMBASE, Cochrane Library, and the Clinical Trials Registry for studies of neoadjuvant ICIs, with or without chemotherapy, in resectable mucosal HNSCC, that explicitly report surgical extent, between 2020-2025 was performed. Two independent reviewers extracted data following PRISMA guidelines. Main outcomes included major pathologic response (MPR), pathologic complete response (pCR), event-free survival (EFS), and overall survival (OS). Study-level proportions were pooled by random effects models. Heterogeneity was assessed by the I2 statistic. RESULTS: The comparative analysis consisted of 4 RAS studies (involving 202 patients) and 11 BPS studies (403 patients). The pooled overall EFS was 83.3% (76.9-88.2) for the former and 82% (75.2-87.2) for the latter (P=.751), and the respective pooled OS was 92.3% (87.5-95.3) and 91.4% (80.3-96.5) (P=.839). The pooled pCR rate was 41.7% (95% CI 5.4-48.4; I2=.0) for RAS and 19.8% (95%CI 13.3-29.6; I2=.62) for BPS (P=.001), while the MPR was not significantly different (59.6%, versus 48.5%, P=.245). RAS was associated with greater organ preservation and reduced need for mandibulectomy and free-flap reconstruction. CONCLUSIONS: RAS following neoadjuvant ICIs in mucosal HNSCC may enable surgical de-escalation with preserved oncologic outcomes and improved function in selected patients. Larger prospective studies are warranted.

Humans↗