Macrophage PABPC4‐SPP1 Axis Orchestrates Immunosuppression in Colorectal Cancer

ABSTRACT Poly(A)‐binding proteins (PABPs) are frequently dysregulated in cancers, yet their functional roles remain largely elusive. Here, we identify that PABPC4, a member of PABPs, is upregulated during colorectal cancer (CRC) progression and associated with poor prognosis. Single‐cell transcriptomics reveals that PABPC4 is predominantly expressed in the macrophages of the tumor microenvironment (TME). Conditional knockout of Pabpc4 in macrophages (C4cKO) profoundly inhibited the progression of multiple cancers, including CRC, melanoma, and ovarian cancer. Mechanistically, C4cKO obviously enhances the local and systemic antitumor immunity, characterized by increased M1‐like macrophages and cytotoxic CD8 + T cells, and reduced M2‐like macrophages and myeloid‐derived suppressor cells. Clearance of macrophages or CD8 + T cells could abolish C4cKO‐stimulated antitumor immunity. We further demonstrate that PABPC4 stabilizes SPP1 mRNA via direct 3′UTR binding, and SPP1 restoration substantially reversed the enhanced antitumor immunity and tumor suppression in C4cKO mice. Clinically, elevated macrophage PABPC4‐SPP1 axis activity in human CRC tissues correlates with immunosuppressive phenotypes, potential immunotherapy resistance, and poor survival of patients. Collectively, our results reveal a previously undiscovered PABPC4‐SPP1 axis in macrophages, which induces tumor‐promoting macrophages and CD8 + T cell dysfunction, thereby facilitating tumor progression. Targeting the PABPC4‐SPP1 axis represents a promising strategy for cancer therapy.