Multimodal targeting of metastatic renal cell carcinoma via CD70-directed allogeneic CAR-NKT cells.

Renal cell carcinoma (RCC) represents about 90% of kidney cancers, with 30%-40% of patients developing metastatic disease despite current treatments. Conventional chimeric antigen receptor (CAR)-T therapy targeting CD70 shows promise but faces challenges due to its autologous, personalized nature. Here, we develop allogeneic CD70-directed CAR-engineered invariant natural killer T (^AlloCAR70-NKT) cells from hematopoietic stem and progenitor cells using a clinically guided culture method. These cells expand robustly with high purity and no fratricide risk. ^AlloCAR70-NKT cells exhibit potent cytotoxicity against primary and metastatic RCC via CAR- and natural killer (NK) receptor-mediated mechanisms and selectively target the immunosuppressive tumor microenvironment (TME) through T cell receptor (TCR) recognition. Additionally, they eliminate CD70⁺ host alloreactive T cells, promoting therapeutic persistence. Taken together, our findings support the therapeutic potential of ^AlloCAR70-NKT cells as a next-generation, off-the-shelf immunotherapy with dual tumor- and TME-targeting functionality and the added capacity to eliminate alloreactive T cells, which offers a compelling strategy for treating metastatic RCC.