WNT11 and CytoF data

Liver metastasis (LM) poses a significant challenge in cancer treatment, with limited therapeutic options and poor prognosis. Understanding the tumor microenvironment (TME) dynamics and immune interactions is crucial for developing effective treatments. Here, we found that WNT11 promoted CD8+ T cell exclusion and suppression and correlated with poor prognosis in liver metastases. Mechanistically, WNT11-overexpressing tumor cells directly reduced CD8+ T cell recruiting and activity via decreasing CXCL10 and CCL4 expression through CAMKII-mediated β-catenin/AFF3 downregulation. Otherwise, WNT11-overexpressing tumor cells promoted immunosuppressive macrophage polarization by inducing IL17D expression via CAMKII/NFκB pathway, which leading to CD8+ T cell suppression. Moreover, CAMKII inhibition potentiated the efficacy of anti-PD-1 therapy in mouse liver metastasis model. Serum WNT11 was identified as a potential minimally invasive biomarker in the management of CRC-LM with immunotherapy. Our findings highlight WNT11/CAMKII axis as a critical regulator of TME and a promising target for immunotherapy in liver metastasis.肝转移（Liver metastasis, LM）是癌症治疗中的重大难题，其临床治疗手段有限且预后不佳。阐明肿瘤微环境（tumor microenvironment, TME）的动态变化与免疫互作机制，对开发高效抗肿瘤治疗策略具有关键意义。本研究发现，WNT11可促进CD8+ T细胞的免疫排除与功能抑制，且与肝转移患者的不良预后显著相关。机制层面，过表达WNT11的肿瘤细胞可通过钙/钙调蛋白依赖性蛋白激酶II（calcium/calmodulin-dependent protein kinase II, CAMKII）介导的β-连环蛋白（β-catenin）/AFF3通路下调CXCL10与CCL4的表达，直接抑制CD8+ T细胞的招募与活性。此外，过表达WNT11的肿瘤细胞可通过CAMKII/核因子κB（nuclear factor kappa B, NFκB）通路诱导白细胞介素17D（IL17D）的表达，进而促进免疫抑制性巨噬细胞极化，最终加剧CD8+ T细胞的功能抑制。进一步实验证实，抑制CAMKII可显著增强抗PD-1疗法在小鼠肝转移模型中的治疗效果。血清WNT11被鉴定为可用于结直肠癌肝转移（colorectal cancer liver metastasis, CRC-LM）免疫治疗管理的潜在微创生物标志物。本研究结果揭示，WNT11/CAMKII信号轴是调控肿瘤微环境的关键调控因子，同时也是肝转移免疫治疗的极具潜力的干预靶点。