Combining local cryoablation with PD-L1 blockade synergistically eradicates established murine lung cancer by modulating mitochondrial in PD-1+CD8+ T cell

•Cryoablation synergized with PD-1 blockade can elicit a robust antitumor immune response.•Anti-PD-L1/cryoablation therapy selectively derived the improvement of depolarized mitochondria in PD-1+CD8+T cells.•Mitochondrial dynamics in CD8+TILs were involved in modulating the local immune response. Immune checkpoint blockade (ICB) has shown improvement in overall survival for lung cancer in clinical trials. However, monotherapies have limited efficacy in improving outcomes and benefit only a subset of patients. Combination therapies targeting multiple pathways can augment an immune response to improve survival further. Here, we demonstrate that combinatorial anti-PD-L1/cryoablation therapy generated a synergistic antitumor activity in the established lung cancer model. Importantly, it was observed that this favorable antitumor immune response comes predominantly from the PD-1+CD8+ T cells generated after the combination therapy, referred as improvement of IFN-γ production and mitochondrial metabolism, which resembled highly functional effectors CD8+ T cells. Notably, the cellular levels of mitochondrial reactive oxygen and mitochondria mass excessively coincided with alteration of IFN-γ secretion in PD-1+CD8+T cell subset. So far, anti-PD-L1/cryoablation therapy selectively derived the improvement of depolarized mitochondria in PD-1+CD8+T cell subset, subsequently rebuild the anti-tumor function of the exhausted CD8+ T cells. Collectively, there is considerable interest in anti-PD-L1 plus cryoablation combination therapy for patients with lung cancer, and defining the underlying mechanisms of the observed synergy.