Remodeling Chondroitin-6-Sulfate–Mediated Immune Exclusion Enhances Anti–PD-1 Response in Colorectal Cancer with Microsatellite Stability

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  • 作者：Wu Qijing, Huang Qiong, Jiang Yu, Sun Fei, Liang Bishan, Wang Jiao, Hu Xingbin, Sun Mengting, Ma Zhenfeng, Shi Yulu, Liang Yanxiao, Tan Yujing, Zeng Dongqiang, Yao Fangzhen, Xu Xin, Yao Zhiqi, Li Shaowei, Rong Xiaoxiang, Huang Na, Sun Li, Liao Wangjun, Shi Min
  • 期刊：Cancer Immunology Research
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Metastatic microsatellite-stable (MSS) colorectal cancer rarely responds to immune checkpoint inhibitors (ICI). Metabolism heterogeneity in the tumor microenvironment (TME) presents obstacles to antitumor immune response. Combining transcriptome (The Cancer Genome Atlas MSS colorectal cancer, n = 383) and digital pathology (n = 96) analysis, we demonstrated a stroma metabolism-immune excluded subtype with poor prognosis in MSS colorectal cancer, which could be attributed to interaction between chondroitin-6-sulfate (C-6-S) metabolites and M2 macrophages, forming the "exclusion barrier" in the invasive margin. Furthermore, C-6-S derived from cancer-associated fibroblasts promoted co-nuclear translocation of pSTAT3 and GLI1, activating the JAK/STAT3 and Hedgehog pathways. In vivo experiments with C-6-S-targeted strategies decreased M2 macrophages and reprogrammed the immunosuppressive TME, leading to enhanced response to anti-PD-1 in MSS colorectal cancer. Therefore, C-6-S-induced immune exclusion represents an "immunometabolic checkpoint" that can be exploited for the application of combination strategies in MSS colorectal cancer ICI treatment.

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