即使在有 T 细胞浸润的肿瘤中，对免疫检查点抑制剂 (ICIs) 的耐药性也很常见。因此，我们研究了 ICI 诱导的 T 细胞浸润在耐药肿瘤微环境中的后果。与 ICI 反应性肿瘤相比，治疗后 ICI 耐药性肿瘤中的 T 细胞和中性粒细胞数量增加。耐药肿瘤的特点是 IL-1 受体 1 (IL1R1) 高表达，能够对 IL-1 和 TNFα 产生协同反应，通过 NF-κB 信号传导诱导 G-CSF、CXCL1 和 CXCL2，支持肿瘤中免疫抑制性中性粒细胞积聚。这种炎症抵抗回路的扰动使肿瘤对 ICI 敏感。矛盾的是，无论在体外还是体内，T 细胞都通过 TNFα 驱动这一抵抗回路。这种炎症抵抗回路及其影响的证据也转化为人类癌症。这些数据支持 ICI 耐药机制，其中治疗诱导的 T 细胞活性可以​​驱动肿瘤对 IL-1 和 TNFα 产生耐药性，具有重要的治疗意义。

Resistance to immune checkpoint inhibitors (ICIs) is common, even in tumors with T cell infiltration. We thus investigated consequences of ICI-induced T cell infiltration in the microenvironment of resistant tumors. T cells and neutrophil numbers increased in ICI-resistant tumors following treatment, in contrast to ICI-responsive tumors. Resistant tumors were distinguished by high expression of IL-1 Receptor 1 (IL1R1), enabling a synergistic response to IL-1 and TNFα to induce G-CSF, CXCL1, and CXCL2 via NF-κB signaling, supporting immunosuppressive neutrophil accumulation in tumor. Perturbation of this inflammatory resistance circuit sensitized tumors to ICIs. Paradoxically, T cells drove this resistance circuit via TNF both in vitro and in vivo. Evidence of this inflammatory resistance circuit and its impact also translated to human cancers. These data support a mechanism of ICI resistance, wherein treatment-induced T cell activity can drive resistance in tumors responsive to IL-1 and TNFα, with important therapeutic implications.