The biological and functional heterogeneity between tumors—both across and within cancer types—poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8⁺ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy.

肿瘤之间的生物学和功能异质性（包括跨癌症类型和癌症类型内部）对免疫治疗构成了挑战。为了了解肿瘤免疫异质性和免疫治疗敏感性的潜在因素，我们从胰腺癌的本土小鼠模型中建立了一个同源肿瘤细胞克隆库。这些克隆产生的肿瘤在植入免疫功能正常的小鼠时概括了 T 细胞发炎和非 T 细胞发炎的肿瘤微环境，具有免疫细胞亚群的不同浸润模式。共同注射肿瘤细胞克隆显示非 T 细胞发炎表型占主导地位，并且瘤内 CD8⁺ T 细胞的定量和定性特征都决定了对治疗的反应。转录组学和表观遗传学分析显示，趋化因子 CXCL1 的肿瘤细胞内在产生是非 T 细胞炎症微环境的决定因素，CXCL1 消融促进 T 细胞浸润和对联合免疫治疗方案的敏感性。因此，肿瘤细胞内在因素塑造肿瘤免疫微环境并影响免疫治疗的结果。