Mechanometabolic regulation of CAR-NK cells in solid tumors: evidence, engineering hypotheses, and translational constraints

CAR-NK cells offer an allogeneic and potentially safer platform for adoptive cell therapy, yet their activity in solid tumors remains inconsistent and often limited by poor trafficking, short persistence, antigen heterogeneity, and suppressive tumor microenvironments. This narrative Review examines an underintegrated dimension of CAR-NK failure: the interaction between metabolic stress and mechanical constraints within solid tumors. We integrate evidence from NK/CAR-NK studies, related T-cell systems, and tumor mechanobiology across three axes: mitochondrial adaptation to hypoxia, lipid handling under nutrient stress, and responses to mechanically restrictive tumor environments. Hypoxia-associated mitochondrial fragmentation has mechanistic support in NK cells, with emerging evidence that DRP1 disruption preserves CAR-NK cytotoxicity under hypoxia. Lipid-associated NK-cell dysfunction is supported across several disease contexts, whereas CPT1A overexpression, SOAT1 inhibition, and GPX4/FSP1 augmentation remain candidate CAR-NK strategies. PIEZO1-dependent NK-cell mechanosensing is experimentally supported, but its proposed coupling to YAP/TAZ-mediated metabolic dysfunction requires direct validation. We propose that future CAR-NK design should combine antigen recognition with context-restricted metabolic and mechanobiological support, including inducible circuits, cytokine armoring, checkpoint editing, and standardized iPSC-derived and donor-derived allogeneic platforms. We distinguish interventions supported by direct preclinical CAR-NK evidence from candidate designs requiring validation, and identify the functional, safety, and manufacturing requirements for further translation.