Deletion of RIAM in myeloid cells accelerates tumor growth by macrophage reprogramming 2248360

Abstract Introduction Myeloid cells within the tumor microenvironment (TME) critically regulate cancer progression. Integrins orchestrate essential myeloid functions, including adhesion, migration, phagocytosis and antigen presentation. Rap1-interacting molecule (RIAM) is an indispensable component of integrin activation machinery. The role of RIAM in tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) is unknown. Methods To investigate this, we generated mice with myeloid-specific RIAM deletion (RIAM fl/fl LysM-Cre ) and implanted MC17-51 fibrosarcoma or B16-F10 melanoma. Results Compared to WT controls, RIAM fl/fl LysM-Cre mice developed significantly larger tumors indicating that RIAM expression in myeloid cells restrains tumor progression. Flow cytometry and RNA sequencing revealed that RIAM-deficient TAMs were skewed toward an M2-like phenotype, with upregulation of CD204, CD206, and CD163, and downregulation of CD86, CD88, and MHC-II. Transcriptomic pathway analysis showed enrichment of IL-4/IL-13 signaling and suppression of NF-κB—mediated inflammatory programs, consistent with impaired pro-inflammatory function. In contrast, RIAM-deficient splenic MDSCs had attenuated immunosuppressive capacity. Thus, despite impaired MDSC activity, RIAM deletion in the myeloid compartment accelerates tumor growth by reprogramming TAMs toward a tumor-promoting state. Conclusion These findings identify RIAM and integrin signaling as novel therapeutic targets for reversing TAM-mediated tumor progression. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)