Na, K-ATPase interaction 1 (NKAIN1) is a transmembrane protein that can interact with Na, K-ATPase β1 subunit. NKAIN1 has prognostic value in several cancers, but its biomarker and carcinogenic roles in the development of prostate adenocarcinoma (PRAD) remain underexplored.
The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were used to analyze the expression and prognostic significance of NKAIN1 in PRAD. The Genomics of Drug Sensitivity in Cancer (GDSC) database and The Cancer Therapeutics Response Portal (CTRP) database were used to analyze drug resistance. Single-cell RNA sequencing was employed to define cell clusters. GO, KEGG, and GSEA enrichment analyses were performed to predict the function of NKAIN1-related factors. Finally, CCK8, Colony formation assay, transwell experiments, and subcutaneous tumor formation in nude mice were conducted to validate the role of NKAIN1 in PRAD development.
NKAIN1 was significantly upregulated in PRAD, correlating with advanced TNM stages, poor survival, and may be involved in drug resistance. High NKAIN1 expression was associated with altered immune infiltration. Additionally, NKAIN-related genes were enriched in Wnt signaling, metabolism, and immune-related pathways. Knockdown of NKAIN1 suppressed PRAD cell proliferation, migration, invasion, and immune evasion in vitro and tumor growth in vivo.
NKAIN1 serves as a prognostic, drug resistance, and immune infiltration marker. Moreover, NKAIN1 promotes PRAD progression and suggests it acts as a potential therapeutic target.
This research has been retrospectively registered in the Ethics Committee institutional of the First Affiliated Hospital of Soochow University with the number of 2025–733.
Advanced renal cell carcinoma frequently acquires resistance to immune checkpoint blockade (ICB), underscoring the pivotal influence of the tumor immune microenvironment (TME) on therapeutic efficacy. While recent studies have implicated multicellular crosstalk within the TME as a central driver of ICB resistance, the precise multicellular programs (MCPs) that orchestrate this process remain poorly defined. Here, through integrative single-cell and spatial transcriptomic profiling of clear cell RCC (ccRCC) cohorts, we delineated a previously unrecognized MCP associated with ICB resistance, distinguished by heightened lysosomal activity, adipogenic signaling, and rewired fatty acid metabolism. Within this program, we uncover a coordinated interplay among TAM_APOE, ccRCC_CXCL14, and endothelial cells, whereby ccRCC_CXCL14 recruits TAM_APOE, which subsequently promotes tumor lipid metabolic reprogramming and angiogenesis, forming a pro-tumorigenic feedforward loop. Spatial mapping revealed a malignant gene topic colocalizing with this MCP in tumor cores, which robustly predicted both unfavorable survival and resistance in ICB-treated patients. Functional assays confirmed that the CXCL14-TAM axis promotes metabolic reprogramming, while dual CXCR4 and PD-1 blockade synergistically reverses the resistant phenotype by restoring CD8⁺ T-cell cytotoxicity. Multiplex immunofluorescence further validated the enrichment of this MCP specifically in non-responders. Collectively, our study defines a spatially organized, functionally coordinated multicellular niche that drives ICB resistance in ccRCC, establishing both a predictive biomarker for patient stratification and a mechanistic framework for therapeutic intervention.
