Sequential axitinib and survivin vaccination unlock curative PD-1 immunotherapy in renal carcinoma.

چکیده اصلی

Despite significant progress achieved by combining VEGFR tyrosine-kinase inhibitors (TKIs) with immune checkpoint inhibitors (ICIs), complete responses remain rare in metastatic renal cell carcinoma (mRCC), highlighting the need for strategies that optimize therapeutic synergy. Here, we show that the efficacy of VEGFR blockade, vaccination, and PD-1 inhibition critically depends on treatment sequence. Using an orthotopic RENCA model, we show that short-term VEGFR inhibition with axitinib transiently remodels tumor vasculature, alleviates hypoxia, and limits suppressive myeloid subsets, thereby generating an immune-permissive window. Administering a survivin-based long-peptide vaccine (SVX) during this preconditioning phase elicits strong Th1-polarized CD4⁺ and cytotoxic CD8⁺ T-cell infiltration, which exhibit a polyfunctional cytokine and chemokine profile. When PD-1 blockade is introduced concomitantly with vaccination, after, rather than during, axitinib treatment, the triple regimen (axitinib + [SVX + anti-PD-1]) achieves durable tumor control with a high rate of complete responses, outperforming all other treatment schedules. Mechanistically, this sequence aligns vascular reprogramming, antigen-specific priming, and checkpoint release, converting an immune-excluded tumor into a T-cell-dominated, cytotoxic niche. Collectively, these findings identify temporal coordination as a critical determinant of therapeutic success and establish a mechanistically grounded framework for integrating vascular preconditionning, tumor-antigen vaccination, and PD-1 blockade as a curative immunotherapy strategy in renal carcinoma.

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