Irgm1-Ifi35 Axis Promotes Renal Cancer Cell Immune Evasion Through Reprogramming the Differentiation of Myeloid-derived Suppressor Cell.

The management of cancers has been revolutionized by PD-1 blockade. However, most renal cell carcinoma (RCC) patients do not respond to anti-PD-1 antibodies. Here, we conducted anti-PD-1 treatment using a mouse model of RCC. We identified an immune-resistant subpopulation with high expression of immunity-related GTPase Irgm1 using a DNA barcoding system integrated with single-cell RNA sequencing. Next, the results of CyTOF analysis demonstrated a significant increase in Ly6ClowLy6G-CCL5+ M2-type macrophages after immunotolerance. These macrophages were differentiated from MDSCs and exhibited greater immunosuppressive capabilities than MDSC precursors. We also established contact between high-Irgm1 tumor cells and MDSC differentiation. We identify the tumor-secreted IFN-induced protein Ifi35 as an inhibitor for the differentiation of MDSCs, and Irgm1 facilitates the autophagic degradation of Ifi35 through p62-dependent selective autophagy, which results in the generation of MDSC-derived strongly immunosuppressive macrophages. We further demonstrated that Ifi35 in combination with anti-PD-1 antibody have synergistic therapeutic benefits for RCC.