Cryoablation Activates the cGAS–STING‐CXCL10 Axis in Macrophages to Enhance Anti‐Tumor Immunity in NSCLC

ABSTRACT Local ablative therapy has emerged as an essential treatment for patients with non‐small cell lung cancer (NSCLC). Whether cryoablation is superior to thermal ablation in the era of immunotherapy and the related mechanism remains undefined. We first observed superior progression‐free survival with cryoablation compared with thermal ablation in patients with oligoresidual disease after immunotherapy. Single‐cell RNA sequencing of human peripheral blood monocyte cells and mouse tumors showed that cryoablation combined with anti‐PD‐1 expanded more CXCL10 ⁺ macrophages than thermal ablation combination. CXCR3 blockade and inhibition of T cells egressing from draining lymph nodes abolished the systemic anti‐tumor efficacy. Mechanistically, tumor DNA released by cryoablation was taken up by macrophages, activating the cGAS–STING signaling pathway, increasing the pool of CXCL10 ⁺ macrophages and CXCL10 secretion. Our study demonstrated that CXCL10 ⁺ macrophages and the CXCR3 ⁺ T cells were critical mediators of the systemic anti‐tumor immunity induced by cryoablation in advanced NSCLC.