Enhancing the fitness of NK cell via olfactory receptor OR7A10: a novel strategy to improve immune therapy for solid tumors

Chimeric antigen receptor (CAR)-based adoptive cell therapies have displayed outstanding efficacy in hematological malignancies; in spite of this, success in solid tumors remains limited. Natural killer (NK) cells have arisen as an encouraging alternative to T cells for cancer immunotherapy owing to their innate cytotoxic capability, negligible risk of graft-vs-host disease (GVHD), and lowered cytokine release syndrome (CRS). Regardless of these improvements, NK cell therapies face substantial challenges in the solid tumor setting, with an immunosuppressive tumor microenvironment (TME), inadequate persistence, and poor metabolic fitness. In a recently published study, Yang et al. utilized a CRISPR-based Synergistic Activation Mediator (SAM) screen to find novel genetic targets capable of improving NK cell anti-tumor function. Using an in vivo screening approach with over 70,000 guide RNAs in an NK92 cell line model bearing colorectal tumors, the investigators identified olfactory receptor OR7A10 as a top-ranked candidate gene. Consequent validation in primary NK cells and third-generation CAR-NK constructs demonstrated that OR7A10 overexpression significantly boosted cytolytic activity among multiple solid tumor types, enriched metabolic fitness through increased oxidative phosphorylation and mitochondrial biogenesis, and conferred resistance to the hostile TME. These results acknowledged OR7A10 as a novel molecular target for engineering next-generation CAR-NK cell products with improved anti-tumor efficacy in solid malignancies¹.