Related Experiment Video
Updated: Oct 9, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Remodeling Chondroitin-6-Sulfate-Mediated Immune Exclusion Enhances Anti-PD-1 Response in Colorectal Cancer with
Qijing Wu1, Qiong Huang1, Yu Jiang1
1Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China.
Abstract:
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.
Insights
Metastatic microsatellite-stable colorectal cancer shows poor response to immune checkpoint inhibitors. Targeting chondroitin-6-sulfate (C-6-S) can reprogram the tumor microenvironment, enhancing treatment efficacy.
Area of Science:
- Oncology
- Immunology
- Metabolism
Background:
- Metastatic microsatellite-stable (MSS) colorectal cancer (CRC) exhibits limited response to immune checkpoint inhibitors (ICIs).
- Tumor microenvironment (TME) metabolic heterogeneity impedes effective anti-tumor immune responses.
- Identifying novel therapeutic targets is crucial for improving MSS CRC treatment outcomes.
Purpose of the Study:
- To investigate the role of metabolic alterations in immune exclusion within the MSS CRC TME.
- To identify specific metabolites and pathways contributing to poor ICI response in MSS CRC.
- To explore C-6-S-targeted strategies for enhancing ICI efficacy in MSS CRC.
Main Methods:
- Combined transcriptome analysis of The Cancer Genome Atlas MSS CRC cohort (n=383) and digital pathology (n=96).
- Investigated the interaction between chondroitin-6-sulfate (C-6-S) and M2 macrophages in the invasive margin.
- Utilized in vivo models to assess C-6-S-targeted strategies and their impact on the TME and anti-PD-1 response.
Main Results:
- Identified a stroma metabolism-immune excluded subtype associated with poor prognosis in MSS CRC.
- Demonstrated that C-6-S, derived from cancer-associated fibroblasts, promotes M2 macrophage accumulation and forms an 'exclusion barrier'.
- Showed that C-6-S activates JAK/STAT3 and Hedgehog pathways via pSTAT3 and GLI1 co-nuclear translocation.
- C-6-S-targeted strategies reduced M2 macrophages, reprogrammed the immunosuppressive TME, and enhanced anti-PD-1 response in vivo.
Conclusions:
- C-6-S-induced immune exclusion acts as an 'immunometabolic checkpoint' in MSS CRC.
- Targeting C-6-S presents a promising strategy for combination therapy to improve ICI efficacy in MSS CRC.
- Reprogramming the immunometabolic TME is key to overcoming ICI resistance in MSS CRC.
