Pan-Cancer Computational Analysis of RKIP (PEBP1) and LKB1 (STK11) Co-Expression Highlights Distinct Immunometabolic Dynamics and Therapeutic Responses Within the Tumor Microenvironment

RKIP and LKB1, encoded by <i>PEBP1</i> and <i>STK11</i>, respectively, have emerged as key regulators of cancer pathophysiology. However, their role in shaping tumor progression through modulation of the tumor microenvironment (TME) is not yet fully understood. To address this, we performed a comprehensive pan-cancer analysis using TCGA transcriptomic data across 33 cancer types, grouped by their tissue of origin. We investigated <i>PEBP1/STK11</i> co-expression and its association with transcriptomic reprogramming in major TME components, including immune, mechanical, metabolic, and hypoxic subtypes. Our results revealed both positive and inverse correlations between <i>PEBP1/STK11</i> co-expression and TME-related molecular signatures, which did not align with classical cancer categorizations. In a subset of tumors, <i>PEBP1/STK11</i> co-expression was significantly associated with improved overall survival and reduced mortality (HR < 1). Notably, we predominantly observed inverse correlations with pro-inflammatory and immunosuppressive chemokines, immune checkpoints, extracellular matrix components, and key regulators of epithelial-to-mesenchymal transition. In contrast, we found positive associations with anti-inflammatory chemokines and their receptors. Importantly, <i>PEBP1/STK11</i> co-expression was consistently linked to reduced expression of drug resistance genes and greater chemosensitivity across multiple tumor types. Our findings underscore the co-expression of <i>PEBP1</i> and <i>STK11</i> as a promising target for future studies aimed at elucidating its potential as a biomarker for prognosis and therapeutic response in precision oncology.