VSIR and neoplasm: Possible contributors to primary and secondary refractory RCC include hypoxia-driven angiogenesis, intra- and intertumoral genetic heterogeneity, immunosuppressive cellular infiltrates (such as regulatory T-cells [T Regs], tumour-associated macrophages [TAMs], and myeloid-derived suppressor cells [MDSCs]), alterations in tumour cell metabolic pathways, expression of alternative immune checkpoints (e.g., LAG-3, VISTA, TIGIT, and TIM-3), and host factors such as the microbiome [32,33].