Convergent immune dysregulation in sepsis and colorectal cancer highlights plasma cells and identifies shared candidate genes

Sepsis and colorectal cancer (CRC) are global diseases that, while distinct in pathophysiology, often co-occur, leading to poor outcomes. Sepsis provokes acute inflammation followed by immunoparalysis, whereas CRC fosters an immunosuppressive tumor microenvironment (TME) that enables immune evasion. Despite these differences, both conditions exhibit a similar immune imbalance, suggesting shared immunoregulatory mechanisms. We integrated multi-cohort bulk and single-cell RNA sequencing (scRNA-seq) datasets from sepsis and CRC, performing differential gene expression, immune-cell infiltration (MCP-counter), and single-sample gene set enrichment (ssGSEA) analyses. We focused on plasma cells (PCs), applying weighted gene co-expression network analysis (WGCNA) to identify PC-associated modules and intersecting their differentially expressed genes (DEGs) to identify shared candidate genes. We assessed their diagnostic performance (ROC/AUC); finally, we examined their expression in an independent peripheral blood scRNA-seq cohort comprising CRC (n = 3) and CRC with sepsis (n = 3). Both diseases showed pronounced adaptive immune exhaustion. PCs were the most consistently enriched immune population across the analyzed sepsis and CRC cohorts and displayed heightened cell cycle–active states. Functional enrichment implicated mitochondrial metabolism, endoplasmic-reticulum stress, ribosome biogenesis, and transmembrane redox processes. CellChat indicated enhanced macrophage migration inhibitory factor (MIF)–mediated PC crosstalk in disease versus healthy states. Integrated analyses identified eight shared candidate genes—CLEC10A, LGALS2, VIPR1, NAAA, RNASE1, PID1, CD36, and CAPN2—that showed potential to discriminate patients from controls across cohorts. In the clinical scRNA-seq cohort, expression remodeling of these genes was observed in CRC patients with sepsis. Sepsis and CRC share convergent immune features, with PCs emerging as prominent contributors to immune dysregulation. These candidate genes may contribute to this shared immune imbalance and provide leads for future biomarker development and mechanistic studies.