Abstract
Renal cell carcinoma with sarcomatoid features (sRCC) is a highly aggressive tumor type yet preferentially responds to immune checkpoint blockade (ICB). To better understand microenvironmental mediators of this paradoxical immune sensitivity, we performed single-cell analyses of human sRCC tumors compared against clear cell RCC (ccRCC), with validation spatially and in bulk transcriptomic datasets totaling over 3,000 RCC tumors. We describe a robust immune network in sRCC using these orthogonal approaches: tumor-infiltrating T cells in sRCC are more activated, and subsequently exhausted, while being enriched for CXCL13 expression. Congruently, tertiary lymphoid structures are pervasive in sRCC, paralleling functional enrichment of humoral immune activity. Tumor clone analysis revealed increased iron-associated programs in sRCC, presenting a potential vulnerability. We furthermore leveraged the paradoxical biology of sRCC to derive a genomic dedifferentiation signature (GDS) that, while negatively prognostic, identifies patients most likely to benefit from ICB across cohorts and tumor types.