HNRNPA2B1 Orchestrates Immune Evasion in Colorectal Cancer by Rewiring Tumor–Immune Cell Interactions and Suppressing CD8+ T-cell Infiltration
Immune checkpoint blockade (ICB) has transformed colorectal cancer therapy, yet the majority of microsatellite-stable colorectal cancers remain refractory because of insufficient tumor-immune cell cross-talk. Identifying molecular regulators that modulate the tumor immune microenvironment (TIME) is crucial for expanding ICB efficacy. In this study, we identified HNRNPA2B1, an RNA-binding protein prominently upregulated in colorectal cancer, as a key driver of immune evasion. Despite low cytotoxicity to normal cells, HNRNPA2B1 rewired the TIME by suppressing Cxcl9/Cxcl10-Cxcr3 signaling, CD8+ T-cell infiltration, and MHC class I antigen presentation, resulting in a noninflamed ("cold") tumor state. HNRNPA2B1 deletion reprogramed the TIME, enhanced CD8+ T cell-mediated tumor clearance, and sensitized microsatellite-stable colorectal cancers to ICB. A computational A2B1 score was developed to quantify HNRNPA2B1's impact on tumor-immune interactions, and it strongly correlated with immune infiltration, epithelial-mesenchymal transition status, and patient prognosis, supporting its potential role as a biomarker for ICB responsiveness in colorectal cancer.
Authors
- Ruhua Liu
- Arabella Wan (ORCID: https://orcid.org/0009-0001-8310-2912)
- Wu Chang Song (ORCID: https://orcid.org/0000-0002-6996-6132)
- Heng Liang (ORCID: https://orcid.org/0000-0002-4054-7364)
- Chuwei Liu (ORCID: https://orcid.org/0000-0003-3473-8102)
- Guohui Wan (ORCID: https://orcid.org/0000-0001-5170-7282)
- Yuyan Zheng
- Xiongbin Lu (ORCID: https://orcid.org/0000-0002-7987-9825)
- Min Xiao
- Zhi Wang (ORCID: https://orcid.org/0000-0002-5276-1413)
- Weiling He (ORCID: https://orcid.org/0000-0003-4061-7382)
- Shijia Yan (ORCID: https://orcid.org/0000-0002-7378-0963)
- Yuan Deng
- Peipei Wang
Institutions
- University of Southern California (US)
- Sun Yat-sen University (CN)
- Xiamen University (CN)
- National Medical Products Administration (CN)
- Pennsylvania Hospital (US)
- First Affiliated Hospital of Xiamen University (CN)
- Guangdong Province Stomatological Hospital (CN)
- Zhongshan Hospital of Xiamen University (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Stomatology Hospital (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine (CN)
- First Affiliated Hospital Zhejiang University (CN)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2025-10-20
- DOI
- https://doi.org/10.1158/2326-6066.cir-25-0433
- Citations
- 1
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.05