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.

肝转移瘤（LM）在癌症治疗中构成重大挑战，其治疗选择有限，预后不良。深入理解肿瘤微环境（TME）的动态变化及免疫相互作用对于开发有效治疗方案至关重要。本研究发现，WNT11促进CD8+ T细胞的排除和抑制，并与肝转移瘤的预后不良相关。机制上，过表达WNT11的肿瘤细胞通过CAMKII介导的β-catenin/AFF3下调，直接减少了CXCL10和CCL4的表达，从而降低CD8+ T细胞的招募和活性。另一方面，过表达WNT11的肿瘤细胞通过CAMKII/NFκB通路诱导IL17D的表达，进而促进免疫抑制性巨噬细胞的极化，导致CD8+ T细胞的抑制。此外，CAMKII的抑制增强了抗PD-1疗法在小鼠肝转移瘤模型中的疗效。血清WNT11被鉴定为CRC-LM免疫治疗管理中的一种潜在微创生物标志物。我们的研究突出了WNT11/CAMKII轴作为TME的关键调节因子，以及作为肝转移瘤免疫治疗的潜在靶点。