Identifying signals in the tumor microenvironment (TME) that shape CD8⁺ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8⁺ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8⁺ TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation. In the TME, monocyte-macrophage lineage cells produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8⁺ TILs promotes dysfunction, with important implications for cancer immunotherapy.

识别肿瘤微环境 (TME) 中塑造 CD8 ⁺ T 细胞表型的信号可以为癌症的新治疗方法提供信息。^{在这里，我们确定了糖皮质激素受体 (GR) 表达和信号从幼稚到功能失调的 CD8 +}肿瘤浸润淋巴细胞 (TIL)的梯度增加。CD8 ^{+中 GR 的条件删除}TILs 改善效应分化，降低转录因子 TCF-1 的表达，并抑制功能失调的表型，最终抑制肿瘤生长。GR 信号转激活多个检查点受体的表达，并在 T 细胞激活时促进功能障碍相关基因的诱导。在 TME 中，单核-巨噬细胞谱系细胞产生糖皮质激素，这些细胞中类固醇生成的基因消融以及对糖皮质激素生物合成的局部药理学抑制改善了肿瘤生长控制。在临床前模型和黑色素瘤患者中，活性糖皮质激素信号传导与对检查点阻断的反应失败有关。因此，CD8 ^{+中的内源性类固醇激素信号}TILs 促进功能障碍，对癌症免疫治疗具有重要意义。