Abstract The dynamic evolution of the immune tumor microenvironment (TME) during targeted therapy is a critical yet poorly understood determinant of treatment response and resistance. While most studies compare immune states before and after treatment, temporal immune changes during therapy remain largely uncharacterized, limiting development of effective combination strategies. Here, we investigated immune dynamics throughout targeted therapy using mouse melanoma models that recapitulate human therapeutic responses. Single-cell RNA sequencing (scRNA-seq) identified an inflection point where the inflamed TME during tumor regression, characterized by robust NK cell infiltration, transitions to an immune-excluded state upon onset of drug-tolerant residual disease. We uncovered a unique macrophage subset that orchestrates NK cell recruitment during regression. Depletion of these macrophages using LysM-cre;iDTR mice significantly reduced NK cell infiltration. Extending these findings to human cancer, longitudinal scRNA-seq analysis of melanoma and lung cancer patient samples revealed dynamic NK cell infiltration during targeted therapy, establishing a direct link between innate immune remodeling and treatment outcome. Unlike prior prognostic studies assessing immune states at single time points, our results provide mechanistic evidence of a temporal relationship between NK cell infiltration and therapeutic efficacy. Together, these findings position immune evolution as a driver of acquired resistance and identify macrophage–NK cell crosstalk as a therapeutically actionable axis to overcome immune exclusion and improve targeted therapy. Citation Format: Chia-Hsin Hsu, Andrew C. White. Cancer acquires therapy resistance by converting immune infiltration to exclusion through NK cell-macrophage interactions abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr A012.
Hsu et al. (2025) studied this question.