Immune checkpoint inhibitors (ICIs) improve cancer survival but can trigger immune-related adverse events. Among these, fulminant myocarditis is an often fatal complication with limited therapies. We developed a mouse model employing cardiomyocyte-restricted antigen expression to define how ICIs drive cardiac autoimmunity. Combined cytotoxic T cell antigen-4 (αCTLA-4) and programmed death-1 (αPD-1) blockade uniquely induced robust expansion of antigen-specific CD8 T cells, myocardial inflammation, and lethal arrhythmias. PD-1 blockade alone permitted the priming and effector differentiation of naive autoreactive CD8 T cells, whereas concomitant CTLA-4 inhibition amplified cardiac pathology. Unexpectedly, myocardial injury was independent of perforin-mediated cytotoxicity but critically depended on T cell-derived TNF, which promoted myeloid recruitment, cytokine production, and arrhythmogenesis. Genetic ablation of CD8 T cell-derived tumor necrosis factor (TNF) or TNF receptor 2 (TNFR2) blockade prevented cardiotoxicity while preserving antitumor efficacy. These findings establish a TNF-TNFR2-driven inflammatory circuit downstream of autoreactive CD8 T cells as a central mechanism of ICI myocarditis and a strategy to uncouple cardiotoxicity from immunotherapy benefits.

Flare incidences of pre-existing rheumatologic diseases in patients with solid tumors receiving immune checkpoint inhibitors: A systematic review and meta-analysis.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet their use carries the risk of ICI-related myocarditis (ICIrM), a rare but potentially fatal adverse event. Although the overall incidence of ICIrM has been described, recent trends and diagnostic shifts remain poorly characterized. We retrospectively reviewed 11,602 patients treated with ICIs at a multi-center institution from 2011 to 2024. ICIrM cases were identified through manual chart review, and baseline characteristics, cardiovascular events, and outcomes were assessed. The study was designed as a descriptive analysis of temporal trends in ICI therapy use and ICIrM. ICIrM occurred in 127 patients (1.1%), with a mean age of 66.7±12.7years and 56.5% male. Median time to onset was 45days (IQR 106). ICI use increased steadily over the past decade, with a marked rise in ICIrM diagnoses in 2023-2024, accounting for 47.2% of all cases. Diagnostic prevalence rose from 0.5% before 2020 to 1.3% after 2020, likely reflecting enhanced recognition due to the implementation of guideline-based diagnostic criteria (Bonaca et al. and ESC-ICOS). Seasonal variation in ICIrM incidence was not observed. The increasing incidence of ICIrM likely reflects improved clinical awareness and diagnostic practices. Continued efforts to optimize surveillance, early detection, and mitigation strategies are essential as ICI use expands globally.

Protein kinase Cι-driven macrophage infiltration mediates immunosuppression in non-small cell lung cancer.

Outcomes and toxicities of immune checkpoint inhibitors in patients with lung cancer and pre-existing autoimmune disease.

High heterogeneity and an immunosuppressive tumor microenvironment (TME) are the core therapeutic bottlenecks of digestive system tumors. Current monotherapies face prominent limitations: immune checkpoint inhibitors (ICIs) yield low overall response rates as single agents, while long-term use of anti-angiogenic drugs (AADs) easily induces tumor resistance. To overcome these drawbacks, AAD-ICI combination therapy has become a research hotspot in this field, whose core synergy lies in coordinated TME modulation. AADs promote vascular normalization and reverse immunosuppressive TME to enhance intratumoral T lymphocyte infiltration, thereby laying a foundation for ICIs to exert anti-tumor effects and reactivating the endogenous anti-tumor immune response. Natural compounds have drawn extensive attention due to their regulatory value in TME remodeling and tumor combination therapy. However, there is still a lack of a comprehensive and systematic summary of their specific roles, molecular mechanisms and latest research progress in anti-angiogenic therapy, ICIs and their combination regimens for digestive system tumors. This deficiency impedes the further development of this research field. To fill this critical void, this review systematically elaborates the underlying mechanisms and clinical advances of AAD-ICI combination therapy for digestive system tumors. It also summarizes the regulatory functions and relevant research evidence of natural compounds in this therapeutic system, including those with dual regulatory effects. Additionally, the review analyzes existing challenges in basic research and clinical application, and outlines future research priorities. This work is expected to provide a valuable reference for the clinical translation and regimen optimization of precision immunotherapy for digestive system tumors.

The clinical efficacy of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) remains limited. Modulation of the glucagon-like peptide-1 receptor (GLP-1R) may enhance T-cell-mediated antitumor responses. The present study aimed to evaluate the antitumor effects of the GLP-1R antagonist Exendin 9-39 (Exe-9) combined with anti-programmed cell death protein-1 (PD-1) treatment in preclinical CRC models. Using in vitro co-culture assays, ELISA and in vivo murine models, alongside immunohistochemical and molecular analyses of clinical samples, HT-29 and MC38-OVA colon cancer cell lines were co-cultured in vitro with activated T cells in the presence of Exe-9. In vivo, male BALB/c mice were injected with MC38 to establish a CRC model and nude mice were used to assess T-cell dependency. To evaluate this synergistic effect, BALB/c mice with CRC were treated with Exe-9, anti-PD-1 or a combination. Additionally, clinical CRC samples were analyzed to assess the association of GLP-1R expression with the immunotherapy response. Exe-9 significantly enhanced T-cell-mediated cytotoxicity in CRC cell lines and reduced tumor growth in immunocompetent CRC mice; however, this effect was not observed in nude mice. Furthermore, combination therapy with the GLP-1R antagonist and anti-PD-1 yielded an improved antitumor effect compared with either treatment alone, and high GLP-1R ex2pression in clinical samples correlated with poor ICI response. These findings suggest that GLP-1R antagonism potentiates T-cell-mediated antitumor immunity and may provide a promising adjunctive therapeutic strategy for patients with CRC when combined with ICIs in the future.

Spatial transcriptomics of immune ecotypes for predicting immunotherapy outcomes in head and neck squamous cell carcinoma.

Circular RNA-mediated tumor immune escape: Mechanistic architecture and nanomedicine-enabled therapeutic reprogramming.

Bridging the translational gap in HNSCC immunotherapy: From resistance mechanisms to high-fidelity preclinical models.

The immune awakening: Transformative strategies against brain tumors.

Real-world outcomes of pembrolizumab-chemotherapy combination in metastatic non-small cell lung cancer by age and sex: A national population-based study.

Innovations in HER2-targeted therapy: A comprehensive review of trastuzumab deruxtecan.

The Central Qi theory in traditional Chinese medicine: Gut microbiota modulation as a strategic target for hepatocellular carcinoma therapy.

Fatty acid synthase (FASN), the key enzyme driving de novo lipogenesis, has emerged as a central metabolic hub in cancer, linking aberrant lipid synthesis to tumor progression, immune escape, and therapy resistance. This review provides a comprehensive overview of the regulatory landscape and oncogenic functions of FASN, highlighting its modulation at transcriptional, post-transcriptional, and post-translational levels. We discuss how FASN-driven lipid remodeling supports tumor proliferation, disrupts antigen presentation, alters immune cell metabolism, and suppresses ferroptosis, thereby enabling resistance to chemotherapy, radiotherapy, targeted therapy, and immune checkpoint inhibitors. Emerging therapeutic strategies-including direct FASN inhibition, targeting upstream regulators, and rational metabolic-immune-ferroptosis combinatorial regimens-are explored in the context of precision oncology. Given the metabolic plasticity of cancer cells and the heterogeneous response of the tumor immune microenvironment, future advances will rely on dynamic biomarker-guided therapy and spatiotemporal profiling of FASN activity. Together, these insights position FASN not merely as a metabolic enzyme but as a versatile therapeutic axis at the intersection of cancer metabolism, immunity, and resistance.

Oligoprogressive disease (OPD) occurs when a limited number of disease sites show progression. Data on OPD incidence during systemic therapy for metastatic non-small cell lung cancer (NSCLC) are increasing, while data on progression patterns after systemic therapy with local radical treatment (LRT) in patients with synchronous oligometastatic disease (sOMD) are limited. We conducted a retrospective multicenter study to assess progression patterns, factors associated with progression and survival outcomes in sOMD NSCLC patients treated with systemic therapy and LRT. Between January 2015 and December 2022, 199 patients were included. With a median follow-up of 68.4months, 78% experienced progression: 63% OPD and 37% widespread PD. Significant differences between OPD and widespread PD were found for performance status (62% WHO PS 0 vs 42%), tumor histology (squamous 13% vs 28%), KRAS mutation (36% vs 26%), N stage (N0-1 40% vs 21%), number (1 metastasis 72% vs 53%), and metastasis location. Patterns of PD were not associated with first-line therapy type (chemo-only vs immune checkpoint inhibitor [ICI]-based). Median PFS and OS were longer for OPD vs widespread PD: median PFS 10.5 (95% CI 8.9-12.1) vs 8.1months (95% CI 7.7-8.6) (p<0.001), median OS 30.9 (95% CI 23.0-38.9) vs 15.2months (95% CI 11.4-18.9), p<0.001. These findings suggest clinical and molecular features reflecting disease biology and may help identify patients likely to develop oligoprogression after combined therapy, a pattern associated with improved PFS and OS. Further prospective studies are needed to better predict progression and select patients benefiting from LRT.

The combination of cancer vaccine and an immune checkpoint inhibitor (ICI) function synergistically to induce effective antitumor immune responses. However, their clinical application is constrained by exacerbated immune-related adverse events (irAEs), notably checkpoint inhibitor-associated pneumonitis (CIP). To address this challenge, a peripheral lymphoid organ-targeted strategy was developed to spatiotemporally modulate T-cell responses through the co-localization of tumor vaccines and anti-PD1 (αPD1). This approach substantially reduced tumor growth and CIP severity by attenuating nonspecific T-cell infiltration in the lungs. In contrast, when tumor vaccines and αPD1 failed to precisely target the same T cell population, the enhanced therapeutic efficacy was at the cost of increased off-target CIP. As a consequence, combined tumor-specific T cells with PD1-blockade performed superior tumor-specific cytotoxicity and preferential tumor infiltration, further augmenting anti-tumor effects while minimizing CIP. These findings provide a homologous lymphoid organ-targeted paradigm that optimizes anti-tumor immune responses with reduced immune-related toxicities, offering a promising strategy for safer and more effective cancer immunotherapy.

Markers of immune activation and immunotherapy responsiveness are increased in 3D Pancreatic cancer organoids when primed with photodynamic- and chemo-therapy.

Conventional radiotherapy compromises antitumor immunity through collateral damage to immune cells. While boron neutron capture therapy (BNCT) enables tumor-selective 10B (n, α) 7Li reactions, clinical agents like boronophenylalanine (BPA) suffer from excessive dosing and exhibit immune-metabolic inertia. We report a biomineralized albumin-based BNCT agent (Albumin@MnB) synthesized from clinically accessible borax, manganese, and albumin, which unlocks neutron capture-triggered immunotherapeutic activation. Albumin@MnB achieves potent tumor suppression at reduced boron doses, demonstrating superior efficacy compared with BPA. Importantly, Albumin@MnB enhances intratumoral immune cell infiltration and suppresses distant tumor growth, synergizing with adoptive T cell immunotherapy and immune checkpoint inhibitors. By integrating tumor-specific radiolytic energy deposition with metabolic reprogramming and immune activation, this strategy establishes boron neutron capture immunotherapy (BNCI) as a multimodal therapeutic paradigm that bridges targeted radiolysis with systemic antitumor immunity.

Hexylaminolevulinic acid in precision medicine: A review of advances in drug delivery and combination therapeutics.