Zoledronic acid enhances the efficacy of immunotherapy in non-small cell lung cancer.

Only a minority of patients benefit from immune checkpoint inhibitors (ICIs) therapy, although they have become the standard of care for patients of non-small cell lung cancer (NSCLC) without driver mutations. Zoledronic acid (ZA) enhances the anti-tumor efficacy of endocrine therapy, chemotherapy and targeted therapy. However, little is known about the effect of ZA on the clinical outcomes of ICIs, or its possible mechanisms.Patients with advanced NSCLC treated with ICIs alone or in combination with ZA were recruited. The clinical efficacy was compared between the two cohorts. We used an LL2 mouse model to confirm the combined effects of ZA with ICIs. Immune cell populations and cytokines in the tumor microenvironment and circulation were assayed and analyzed.The median PFS for the patients treated with and without ZA was 5.4 months and 2.8 months, respectively. The combination group showed a higher rate of disease control. In the mouse LL2 lung cancer model, tumor growth was significantly inhibited in mice treated with the combination treatment. More CD8 + IFN-γ + T cells and γδ T cells, and fewer CD11b cells were found in the circulation and TILs in the combination group. Anti-tumor cytokines INF-γ and IL-18 were elevated in the sera after combination therapy.Our study provides preclinical and clinical evidence to show that ZA could improve the therapeutic effects of ICIs. This effect was likely related to the activation of immune cells and elevated cytokines, which provided a new way to improve the effect of ICIs therapy, and is worth exploring further.