口腔鳞状细胞癌 (OSCC) 是 HNSC 最常见的侵袭性形式，以铂类化疗作为初始治疗。然而，对铂类药物产生的获得性耐药性和神经毒性对治疗局部晚期 OSCC 提出了重大挑战。值得注意的是，IDO1 CAF 可以促进 OSCC 进展的免疫抑制 TME。因此，我们开发了一种有效的 IDO1 抑制剂 navoximod，通过在 SCC-9 共培养的 IDO1 /IDO1- CAF 和 SCC-7/IDO1 CAF 接种的小鼠中与顺铂协同的抗肿瘤免疫作用来克服化学免疫耐药性。对 IDO1 CAF 共培养 OSCC 癌细胞的体外生物学测定表明，纳伏莫德与顺铂联合使用可以通过抑制 p 来阻断 IDO1 CAF 分泌的犬尿氨酸 (Kyn)-芳基烃受体 (AhR)-IL-6，从而减轻化疗免疫耐药性。 -STAT3/NF-κB 信号和停止 AhR 诱导的 pol δ 丢失引起的染色体不稳定 (CIN)。此外，该组合通过减少 IDO1 CAF 分泌的 Kyn/AhR 并在 SCC-7/IDO1 CAF 接种的 BALB/c 小鼠中赋予 pol δ 来引发抗肿瘤免疫。同时，该组合可以阻断顺铂引起的神经毒性，并且不干扰化疗。总而言之，该研究调查了纳伏莫德与顺铂联合治疗的潜在治疗潜力，通过减轻 IDO1 CAF 分泌的免疫抑制和 CIN 引起的顺铂耐药性来减轻肿瘤免疫耐药性，为联合化疗-免疫疗法延长肿瘤患者的生存提供了范例。 OSCC.版权所有 © 2023。由 Elsevier Inc. 出版。

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-κB signals and ceasing AhR-induced loss of pol ζ-caused chromosomal instability (CIN). Moreover, the combination elicited antitumor immunity via reducing IDO1+ CAFs-secreted Kyn/AhR and conferring pol ζ 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.Copyright © 2023. Published by Elsevier Inc.