Immunotherapy plus tyrosine kinase inhibitor (IO-TKI) has become the standard first-line therapy for advanced renal cell carcinoma (RCC). However, the modest response rate of IO-TKI therapy and the absence of biomarkers limited the selection of treatment strategies for RCC patients. There were three cohorts enrolled: two from our facility (ZS-MRCC and ZS-HRRCC) and one from a clinical study (JAVELIN-101). By RNA sequencing, the expression of ADAM9 in each sample was measured. By flow cytometry and immunohistochemistry, immune infiltration and T cell function were examined. Primary outcomes were established as treatment response and progression-free survival (PFS). Patients with low-ADAM9 expression had a higher objective response rate (56.5% vs 13.6%, P = 0.01) and longer PFS in both cohorts. In the ZS-HRRCC cohort, the expression of ADAM9 was associated with increased tumor-infiltrating T cells, which was proved by immunohistochemistry (P < 0.05) and flow cytometry (Spearman’s ρ = 0.42, P < 0.001). In the high-ADAM9 group, CD8⁺ and CD4⁺ T cells revealed an exhausted phenotype with decreased GZMB (Spearman’s ρ = − 0.31, P = 0.05, and Spearman’s ρ = − 0.49, P < 0.001, respectively), and fewer Macrophages were identified. A predictive RFscore was further constructed by random forest approach, involving ADAM9 and immunologic genes. Only in the subgroup with the lower RFscore did IO-TKI outperform TKI monotherapy. High-ADAM9 expression was associated with immunosuppression and IO-TKI resistance. Expression of ADAM9 was also associated with the exhaustion and dysfunction of T cells. ADAM9-based RFscore has the potential to be used as a biomarker to distinguish the optimal patient treatment methods between IO-TKI and TKI monotherapy.

免疫疗法联合酪氨酸激酶抑制剂（IO-TKI）已成为晚期肾细胞癌（RCC）的标准一线疗法。然而，IO-TKI 治疗的适度反应率和生物标志物的缺乏限制了 RCC 患者治疗策略的选择。共招募了三个队列：两个来自我们的机构（ZS-MRCC 和 ZS-HRRCC），一个来自临床研究 (JAVELIN-101)。通过 RNA 测序，测量每个样品中 ADAM9 的表达。通过流式细胞术和免疫组织化学，检查免疫浸润和T细胞功能。主要结果确定为治疗反应和无进展生存期 (PFS)。低 ADAM9 表达的患者具有更高的客观反应率（56.5% 对 13.6%，P = 0.01) 和两个队列中更长的 PFS。在 ZS-HRRCC 队列中，ADAM9 的表达与肿瘤浸润性 T 细胞增加有关，免疫组化 ( P  < 0.05) 和流式细胞术 (Spearman's ρ  = 0.42, P  < 0.001)证明了这一点。在高 ADAM9 组中，CD8 ⁺和 CD4 ⁺ T 细胞显示耗竭表型，GZMB 减少（Spearman 的ρ  = − 0.31，P  = 0.05，Spearman 的ρ  = − 0.49，P < 0.001，分别），并且鉴定出更少的巨噬细胞。通过随机森林方法进一步构建预测性 RFscore，涉及 ADAM9 和免疫基因。只有在 RFscore 较低的亚组中，IO-TKI 优于 TKI 单一疗法。ADAM9 高表达与免疫抑制和 IO-TKI 耐药相关。ADAM9 的表达也与 T 细胞的耗竭和功能障碍有关。基于 ADAM9 的 RFscore 有可能用作生物标志物，以区分 IO-TKI 和 TKI 单一疗法之间的最佳患者治疗方法。