Reviving cancer vaccines in renal cell carcinoma: a new chapter in immunotherapy for kidney cancer

Abstract

Renal cell carcinoma (RCC) remains one of the most immunologically responsive solid tumors, yet durable benefit from immune checkpoint inhibitors (ICIs) is achieved in only a subset of patients. Although ICIs are conventionally thought to primarily act by reinvigoration and expanding preexisting antitumor T-cell responses, their ability to consistently broaden tumor-specific immunity remains limited, highlighting a potential role for therapeutic cancer vaccines in RCC to expand, activate, and diversify tumor-targeting T-cell populations. Vaccine strategies in RCC have evolved from broad autologous whole tumor antigen (WTA) approaches to defined tumor-associated antigen (TAA) platforms and, more recently, personalized neoantigen vaccines enabled by next-generation sequencing. Early WTA vaccines demonstrated feasibility and immunogenicity, particularly in the adjuvant setting, but failed to consistently improve survival in metastatic disease. TAA-directed vaccines targeting Wilms’ tumor 1, survivin, mucin 1, carbonic anhydrase IX, and 5T4 confirmed on-target immune activation but yielded limited clinical benefit. Personalized neoantigen vaccines, particularly in high-risk resected clear cell RCC, have shown robust and durable T-cell responses with encouraging early clinical signals and are being investigated in larger clinical trials. However, vaccine efficacy in RCC is constrained by tumor-intrinsic immune suppression, heterogeneous antigen presentation, and subtype-specific tumor immune microenvironments. Emerging strategies to further modulate immunosuppressive signals from tumor cells and the microenvironment may enhance vaccine responsiveness, particularly in immune-cold subtypes. Future progress will require stage-specific application, improved antigen selection, and rational combinatorial approaches tailored to RCC biology.