Synergetic impact of combined navoximod with cisplatin mitigates chemo-immune resistance via blockading IDO1+CAFs-secreted Kyn/AhR/ IL-6 and pol -prevented CIN in human oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is the most prevalent aggressive form of HNSC and treated with platinum based chemotherapy as initial therapy. However, the development of acquired resistance and neurotoxicity to platinum agents poses a significant challenge to treat locally advanced OSCC. Notably, IDO1+ CAFs could promote immunosuppressive TME for OSCC progression. Therefore, we developed a potent IDO1 inhibitor navoximod to overcome chemo-immune resistance via an antitumor immune effect synergized with cisplatin in SCC-9 co-cultured IDO1+/IDO1- CAFs and SCC-7/IDO1+ CAFs-inoculated mice. The in vitro biological assays on IDO1+ CAFs co-cultured OSCC cancer cells supported that combined navoximod with cisplatin could mitigate chemo-immune resistance through blockading IDO1+ CAFs-secreted kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-IL-6 via suppressing p-STAT3/NF-kappa B signals and ceasing AhR-induced loss of pol zeta-caused chromosomal instability (CIN). Moreover, the combination elicited antitumor immunity via reducing IDO1+ CAFssecreted Kyn/AhR and conferring pol zeta in SCC-7/IDO1+ CAFs-inoculated BALB/c mice. Meanwhile, the combination could block cisplatin-induced neurotoxicity and not interfere with chemotherapy. Taken together, the study investigated the promising therapeutic potential of combined navoximod with cisplatin to mitigate tumoral immune resistance via alleviating IDO1+ CAFs-secreted immune-suppression and CIN-caused cisplatin resistance, providing a paradigm for combined chemo-immunotherapy to prolong survival in patients with OSCC.