Abstract
BACKGROUND: KDELR2, a retrograde transport receptor involved in ER protein homeostasis, has emerged as a potential contributor to cancer development. However, its comprehensive expression profile and immunological roles across diverse human tumors remain unclear. METHODS: We performed an integrative pan-cancer analysis of KDELR2 using the TCGA and GTEx datasets, and examined its expression patterns, genetic alterations, methylation status, prognostic significance, and associations with immune infiltration and hallmark cancer pathways. Functional insights were derived from GSEA, GSVA, and immune landscape analyses. Wound healing, transwell and sphere formation assays were performed to investigate the role of KDELR2 in the stem-like properties, migration and invasion of pancreatic cancer cells. RESULTS: KDELR2 was broadly overexpressed in various tumor types and significantly associated with advanced tumor stages and poor clinical outcomes. Copy number amplification was the predominant genomic alteration, while promoter hypomethylation also contributed to its dysregulation. KDELR2 expression was correlated with the activation of oncogenic pathways, including those related to the ER stress response, glycosylation, and membrane trafficking. Moreover, KDELR2 was linked to immunosuppressive microenvironmental features, including enrichment of Tregs, TAMs, and MDSCs and reduced infiltration of cytotoxic immune cells. These trends were validated across multiple immune databases. KDELR2 also showed strong associations with immune checkpoint molecules and chemokine signaling networks, suggesting a dual role in tumor progression and immune evasion. Additionally, in vitro experiments revealed that KDELR2 overexpression promoted the stem-like properties, migration and invasion of PANC-1 cells, whereas KDELR2 knockdown led to the opposite results. CONCLUSION: KDELR2 serves as a potential pan-cancer biomarker associated with tumor aggressiveness and immune modulation. Our findings support KDELR2 as a promising candidate for prognostic evaluation and targeted intervention, particularly in the context of immunotherapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-025-03975-1.