The PTPN6-THBS1 axis drives immunosuppression in renal cell carcinoma by polarizing M2 tumor-associated macrophages

Renal cell carcinoma (RCC) is characterized by a complex and highly heterogeneous tumor microenvironment (TME), the regulation of which remains incompletely understood. This study systematically investigated the role of protein tyrosine phosphatase non-receptor type 6 (PTPN6) in RCC. Through integrated bioinformatics analysis of TCGA and GEO datasets, we found PTPN6 was consistently overexpressed in multiple cancers, including clear cell (KIRC) and papillary (KIRP) RCC subtypes, where it served as a robust diagnostic marker. Elevated PTPN6 specifically correlated with advanced stage, metastasis, and poor survival exclusively in KIRC. Functional assays in renal carcinoma cells revealed that PTPN6 knockdown minimally affected short-term migration but modestly reduced long-term clonogenic potential. Critically, PTPN6 expression strongly correlated with an immunosuppressive TME signature, enriched stromal/immune scores, and infiltration of M2 macrophages and Tregs. In vitro co-culture experiments and transcriptome sequencing established a mechanistic axis whereby PTPN6 in tumor cells promotes M2 macrophage polarization via upregulation of thrombospondin 1 (THBS1). Furthermore, high PTPN6 expression defined a coherent immunosuppressive landscape and identified a patient subgroup (high PTPN6/low cytolytic activity) with the worst prognosis. Finally, PTPN6 expression was linked to distinct drug sensitivity profiles, and in silico docking supported its potential as a direct pharmacological target. In conclusion, our work establishes PTPN6 as a multifaceted promoter of immunosuppressive microenvironment remodeling and a pivotal regulator of the TME in RCC, positioning it as a promising prognostic marker and a new therapeutic target.