Regression-Associated Macrophages Recruit Natural Killer Cells that Constrain Targeted Therapy Resistance.

Abstract

Targeted kinase inhibitors induce marked tumor regressions but are limited by the emergence of drug-tolerant residual disease and resistance. Although tumor-intrinsic and adaptive immune mechanisms have been extensively studied, a better understanding of the contribution of innate immunity to targeted therapy durability is needed to devise optimal treatment strategies. Here, we showed that natural killer (NK) cells constrain targeted therapy resistance and identified a regression-associated macrophage program that promotes NK cell recruitment. In immunocompetent melanoma models that recapitulate patient treatment trajectories, tumor regression was characterized by robust NK infiltration, which transitioned to an NK-excluded residual state preceding resistance. A regression-associated macrophage subset (F4/80hiCCL5⁺MHCII⁺CD63⁺) contributed to NK cell recruitment via CCR2/5 signaling. Genetic depletion of macrophages using LysM-cre;iDTR mice impaired NK cell infiltration. Pharmacologic inhibition of PTPN22, a negative regulator of immune activation, reprogrammed the residual tumor microenvironment, restored NK cell recruitment, and delayed resistance onset. Analysis of patient tumor datasets from melanoma and lung cancer revealed concordant NK dynamics during therapy, linking this innate immune program to clinical outcomes. These findings identify innate immune remodeling as a key contributor to targeted therapy durability and identify NK cell recruitment, promoted in part by regression-associated macrophages, as a therapeutically actionable node for extending durability of response across oncogene-driven cancers.