RAD21 drives tumor progression and confers anti-PD-1 resistance by reprogramming tumor-associated macrophages via upregulation of CSF1 signaling

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, primary and acquired resistance, driven largely by tumor cell-mediated remodeling of the immunosuppressive tumor microenvironment (TME), limit durable responses in most patients. The cohesin subunit RAD21 exhibits frequent copy number variation (CNV) across human cancers, yet its role in modulating tumor immunity remains poorly defined. Here, we identify RAD21 as a frequently amplified oncogene that promotes tumor cell proliferation and metastasis and whose elevated expression correlates with poor patient survival. Mechanistically, RAD21 drives M2-like polarization of tumor-associated macrophages (TAMs) via upregulation of CSF1 signaling, thereby fostering an immunologically "cold" tumor and conferring resistance to anti-PD-1 therapy. RAD21 depletion reverses this immunosuppressive phenotype and, when combined with anti-PD-1 blockade, achieves maximal tumor regression. Our findings unveil a previously unrecognized oncogenic mechanism wherein RAD21 orchestrates immune evasion through activation of CSF1 signaling and position RAD21 as a promising therapeutic target to overcome resistance to anti-PD-1 blockade.

Keywords: CSF1; Immunotherapy; RAD21; Tumor-associated macrophages.