Proteasome inhibition by bortezomib augments the efficacy of anti-PD-L1 therapy against lung cancer.

Given the success of proteasome inhibitors in treating hematological malignancies, we explored whether targeting proteasomes could increase the efficacy of immunotherapy against solid tumors. In a Lewis lung carcinoma (LLC) tumor model, the proteasome inhibitor bortezomib (BTZ) significantly enhanced anti-PD-L1 therapy. Mechanistic analyses revealed that the IFN-γ response gene signature and signaling pathway were significantly increased in tumors treated with the combination of BTZ and anti-PD-L1 therapy compared with those treated with anti-PD-L1 therapy alone. BTZ in vitro increased the responsiveness of lung cancer cells to IFN-γ by stabilizing IFN-γ receptor α chain (IFNGR1) expression. BTZ also enhanced IFN-γ-triggered DNA damage and STING activation. The BTZ-mediated increase in IFN-γ signaling contributed to improved anti-PD-L1 efficacy, as the effect was reduced in IFNGR1-deficient tumors. Compared with standard chemoimmunotherapy, PD-L1 blockade combined with BTZ had greater antitumor effects because of the inability of cisplatin (CDDP) and pemetrexed (PEM) to regulate IFNGR1 expression. BTZ even restored the sensitivity of alanine-serine-cysteine transporter-deficient tumors, which express low levels of IFNGR1, to anti-PD-L1 therapy. Notably, compared with BTZ treatment alone, anti-PD-L1 therapy increased BTZ tumor accumulation by promoting microvascular maturation, potentially addressing a major obstacle to the use of BTZ in solid tumors. Taken together, these results suggest that BTZ, when combined with immunotherapy, holds great promise for treating lung cancer.