Role of VISTA/TIM3 heterodimerization and macrophage metabolic reprogramming in microsatellite stable colorectal cancer.

作者：Fei Sun, Na Hong, Chunting Zeng, Jian Li, Chunhui Gu, Qijing Wu, Qiong Huang, Min Shi · 发表于：Journal of Clinical Oncology · 年份：2026 · DOI：10.1200/jco.2026.44.16_suppl.e15586 · 研究领域：Cancer Mechanisms and Therapy、Galectins and Cancer Biology、Immune cells in cancer

e15586 Background: Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibodies, represent a major paradigm shift in cancer management. However, microsatellite stable (MSS) colorectal cancer (CRC), which accounts for over 95% of CRC cases, exhibits a dismal response rate of less than 5%. Increasing evidence suggests that heterogeneity and complex crosstalk among immune checkpoints limit the efficacy of monotherapy strategies. This study aims to break through current therapeutic bottlenecks by systematically profiling the immune checkpoint landscape of MSS CRC to identify core drivers of immune tolerance and explore novel intervention strategies. Methods: We collected tumor tissues from a multicenter cohort of treatment-naive MSS CRC patients. The immune checkpoint landscape was constructed using flow cytometry, multiplex immunofluorescence, and integrated analysis of public single-cell RNA sequencing and TCGA datasets. To elucidate molecular mechanisms and metabolic characteristics, we employed tumor-bearing mouse models combined with metabolomics, co-immunoprecipitation, and site-directed mutagenesis assays. Results: We identified four distinct immune checkpoint patterns in MSS CRC, among which the VISTA/TIM3 co-expression pattern (14.6%) was most strongly associated with poor prognosis and CD8 + T cell exhaustion. Clinical validation confirmed a specific enrichment of VISTA + TIM3 + tumor-associated macrophages (TAMs) in the tumor microenvironment of approximately...