Cryo-thermal therapy reprograms myeloid cells into CCL5+ mature phenotype to increase T cell infiltration and potentiates anti-PD-1 therapy

ABSTRACT: Although immune checkpoint blockade (ICB) represented by anti-PD-1 therapy has demonstrated significant clinical benefits, its efficacy remains limited by the immunosuppressive tumour microenvironment (TME). Cryo-thermal therapy (CTT) not only completely ablates local solid tumours by pre-freezing before radiofrequency heating, but also reverses immunosuppression and triggers strong systemic anti-tumour immunity to inhibit tumour recurrence and metastasis. Our present study reveals that combining CTT with anti-PD-1 treatment potently enhances myeloid cell maturation and simultaneously promotes the infiltration and functional activation of T cells in distal tumours, resulting in superior suppression of distal tumour growth compared to either cryoablation or radiofrequency ablation combined with anti-PD-1. 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 tumours, creating a cytokine loop where IFN-γ derived from T cells and TNF-α derived from myeloid cells collectively promote CCL5 secretion in myeloid cells to enhance effector T cell recruitment in distal tumours. Subsequently, after CTT, anti-PD-1 treatment amplifies this cascade by enhancing TNF-α production in T cells, and high levels of IFN-γ and TNF-α in distal tumours promotes higher secretion of CCL5 in myeloid cells, resulting in robust infiltration of 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE314594 | GEO | 2026/03/01

REPOSITORIES: GEO