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.

Keywords: CXCL10+ macrophages; NSCLC; cGAS‐STING signalling; cryoablation.