Investigating Novel Immunotherapy Targets in Metastatic RCC

In an interview at the 2026 ESMO Congress, Rahul Winayak, MD, postdoctoral fellow at City of Hope, discusses emerging therapeutic targets in metastatic renal cell carcinoma (mRCC) and the need for new treatment strategies for patients whose disease progresses following immunotherapy-containing regimens.

A poster Winayak and colleagues presented at the Congress examined 4 targets being investigated through early-phase therapeutic approaches: GPR65, HPK1, ENPP3, and CD70. These targets represent distinct mechanisms for addressing tumor growth and immune evasion in RCC.

Winayak explains how GPR65 senses acidity in the tumor microenvironment and contributes to immunosuppression in clear cell RCC, making it a potential target for therapeutic intervention. He also discusses HPK1, an intracellular regulator of T-cell activation that represents an alternative approach to targeting immune checkpoints beyond established cell-surface pathways.

Winayak also explores ENPP3, a surface protein highly expressed in clear cell RCC that is being targeted with bispecific T-cell engagers. These agents are designed to bring tumor cells and T cells together to promote an antitumor immune response. Additionally, he highlights CD70, another cell-surface target being investigated in RCC, including through chimeric antigen receptor (CAR) T-cell therapies.

As treatment resistance remains a challenge in mRCC, Winayak discusses how investigating targets with different biological functions could expand therapeutic options for patients who need additional treatment strategies. Further clinical investigation will be needed to establish the safety and efficacy of these emerging approaches.