TKI resistance is associated with immune dysfunction in ccRCC

In the management of advanced clear cell renal cell carcinoma (ccRCC), antiangiogenic tyrosine kinase inhibitors (TKIs) provide limited long-term durability, even when combined with immune checkpoint blockade (ICB), and the underlying mechanisms remain poorly understood. In this study, we applied 10x Genomics Xenium profiling using a 5,000-gene panel to characterize the tumor ecosystem in TKI-treated vs. untreated ccRCC to identify the escape mechanisms and propose strategies to overcome them. Sunitinib treatment triggered a profound collapse of the vascular and perivascular niche, but induced a more inflammatory yet immunosuppressive tumor microenvironment. Sunitinib did not significantly influence the overall abundance of tumor-associated macrophages (TAMs). However, the spatial organization and intercellular interactions of TAMs were markedly altered, shifting from sequestration alongside endothelial cells to increased communication with T cells. We further identified two TAM subsets—interferon-primed TAMs (IFN-TAMs) and proliferating TAMs (Prolif-TAMs)—that were enriched in sunitinib-treated tumors and associated with shorter progression-free survival. IFN-TAMs displayed strong IFNg signaling activity, elevated PD-L1/PD-L2 expression, and engagement with multiple cell types, including PD-1⁺ T cell subsets. In contrast, Prolif-TAMs expressed distinct tumor-promoting molecules, including CSF1R, MSR1, VSIG4, and TREM2 , and predominantly interacted with tumor cells rather than immune cells. Notably, IFN-TAMs and Prolif-TAMs exhibited high expression of the A2A adenosine receptor ( A2AR ), while T-cell subsets expressed ENTPD1 , enabling adenosine production and A2AR-mediated suppression. In an animal model, PD-1 blockade and pharmacologic inhibition of A2AR signaling potentiated the therapeutic efficacy of axitinib. Collectively, these findings demonstrate that sunitinib promotes an immunosuppressive tumor microenvironment that contributes to therapeutic resistance through macrophage reprogramming and spatial redistribution. Targeting these macrophage subsets may represent a promising strategy to improve the efficacy of TKI-based therapies.