Immunosuppressive cell populations as potential drivers of extrinsic immune checkpoint inhibition resistance in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is an immunogenic cancer in which the use of Immune checkpoint inhibitors (ICIs) has provided clinical benefit. However, long-term therapeutic benefit is limited, as some do not respond initially while others develop resistance after treatment. Although extensive studies have been conducted on tumor intrinsic mechanisms, cells within the tumor microenvironment are also recognized as extrinsic factors in ICI resistance. A critical evaluation of the roles of tumor-associated macrophages, regulatory T cells, myeloid-derived suppressor cells, dysfunctional CD8+ T cells, natural killer cells, and dendritic cells in driving immune dysfunction in ccRCC has been provided in this narrative review. The evidence reviewed in this article suggests that these cell populations collectively impair antigen presentation, effector-cell activation, and cytotoxic function, while also promoting an immunosuppressive microenvironment. However, most of this evidence is collected from mechanistic or prognostic studies rather than from ICI-treated ccRCC cohorts. A single immune cell population cannot explain overall resistance to checkpoint blockade. Instead, resistance to ICIs due to extrinsic factors appears to result from multiple interactions among several immune cell populations. This emphasizes the need for studies that examine the function of immune cells in relation to ICIs to distinguish mechanisms that directly drive resistance to ICIs from general prognostic immune dysfunction.