Abstract
Although immune checkpoint blockade (ICB) represented by anti-PD-1 therapy has demonstrated significant clinical benefits, its efficacy remains limited by the immunosuppressive tumor microenvironment (TME). Our study revealed that the combination of Cryo-thermal therapy (CTT) and anti-PD-1 therapy suppresses the distal tumor growth compared to either cryoablation or radiofrequency ablation combined with anti-PD-1 therapy. Mechanistically, CTT specifically induces TNF-α production in mature myeloid cells, triggering autocrine CCL5 secretion that recruits peripheral IFN-γ+ T cells induced by CTT in distal tumors, creating a cytokine loop in which IFN-γ derived from T cells and TNF-α derived from myeloid cells collectively promote CCL5 secretion in myeloid cells to increase effector T-cell recruitment in distal tumors. After CTT, anti-PD-1 treatment amplifies this cascade by enhancing TNF-α production in T cells. The parallel activation of STAT1 by IFN-γ and NF-κB by TNF-α in myeloid cells converges to drive IRF7-dependent CCL5 upregulation to create a local immune enhancing environment via CCL5-mediated recruitment of T cells. Our study demonstrates that CTT establishes an immunologically favorable TME by reprogramming immunosuppressive myeloid cells into mature myeloid cells with high CCL5 production, thereby facilitating effector T-cell recruitment, providing an efficient therapeutic strategy to promote the response to anti-PD-1 therapy.