MARCO+ Tumor‐Associated Macrophages Impede CD8+ T Cell Immunity to Facilitate Immunotherapy Resistance in Renal Cell Carcinoma

Immune checkpoint blockade (ICB) therapy, especially in combination regimens, has significantly increased survival of renal cell carcinoma (RCC) patients. However, the ICB-resistant mechanisms remain largely unclear and require further investigation. Here, an immunosuppressive ecosystem in ICB-resistant tumors is identified, featured by preferential infiltration of MARCO+ tumor-associated macrophages (TAMs) and restrained cytotoxicity of CD8+ cytotoxic T lymphocytes (CTLs). The infiltrated MARCO+ TAMs can obstruct the development of CD8+ CTLs by impairing MHC-I-mediated neoantigen cross-presentation. Mechanistically, MARCO up-regulates the expression of SOCS1, which obstructs the kinase activity of JAK1, thereby downregulating MHC-I expression through the inhibition of the JAK1-STAT1-NLRC5 signaling cascade. Further, MARCO blockade significantly facilitates ICB therapy in in vivo models by recovering tumor recognition and priming anti-tumor CD8+ T cell responses. Taken together, these findings highlight MARCO as a highly desirable target in ICB-refractory individuals for immunorecognition reignition and immunotherapy modulation.