Background: While programmed death 1 (PD-1) inhibitors have shown remarkable efficacy and survival benefits in lung cancer, their clinical utility is limited when used alone. This study aims to investigate the underlying mechanism by which sodium butyrate (NaB), combined with PD-1 inhibitors, enhances immunotherapeutic efficacy of lung cancer via modulating the signal transducer and activator of transcription 1 (STAT1)/Indoleamine 2, 3-dioxygenase 1 (IDO1)-activated tryptophan (Trp)-kynurenine (Kyn) pathway.

Methods: To assess the effect of combining NaB with a PD-1 inhibitor on lung cancer, we employed a comprehensive array of techniques, including live animal imaging, hematoxylin and eosin (H&E) staining, immunohistochemical analysis, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and various biochemical tests.

Results: Our findings indicated that NaB had the potential to dramatically slow down tumor progression, promote cancer cell death, decrease the ratio of kynurenine to tryptophan, boost the efficacy of PD-1 inhibitors through impeding STAT1/IDO1 pathway (p < 0.05), thereby bolstering the body's anti-cancer response. Meanwhile, co-administration of NaB and PD-1 inhibitor activated CD8⁺ T cells to trigger apoptosis, inhibited tumor cell proliferation, and reduced the Kyn content in vitro (p < 0.05). Moreover, NaB, coupled with a PD-1 inhibitor, down-regulated p-STAT1, IDO1, and programmed death-ligand 1 (PD-L1) protein expression in CD8⁺ T cells and Lewis lung carcinoma (LLC) co-cultured system (p < 0.05). However, the occurrence of the above results was abolished by 2-(1, 8-Naphthyridin-2-yl)phenol (2-NP) or 6-Formylindolo[3, 2-b]carbazole (FICZ) (p < 0.05).

Conclusion: Collectively, our findings revealed that NaB ameliorates the immunosuppressive surroundings in lung cancer and enhances the effect of PD-1 inhibitor through STAT1/IDO1-mediated tryptophan and kynurenine metabolism.