Metabolic and signaling interplay in the adipocyte-tumor microenvironment

Adipocytes are now recognized as active regulators of cancer progression and therapy resistance. Through metabolic, immune, and signaling interactions, they promote tumor cell proliferation, stemness, and survival. This review examines adipocyte tumor crosstalk in triple-negative breast cancer (TNBC) and oral squamous cell carcinoma (OSCC), focusing on how adipocyte-derived mediators influence tumor aggressiveness and treatment outcomes. Important adipocyte-secreted factors including complement C3, CXCL12, leptin, and adiponectin drive oncogenic signaling pathways that support tumor growth. In OSCC, C3/C3aR activation enhances cancer stemness, while in TNBC, bisphenol A-induced CXCL12 activates the CXCL12/CXCR4-PI3K/AKT axis, promoting epithelial-mesenchymal transition and therapy resistance. Additionally, circular RNAs and metabolic enzymes such as GCLC regulate HIF-1α, NF-κB, β-catenin, and mTOR pathways, further sustaining tumor progression. By establishing a tumor-supportive niche, adipocytes contribute significantly to therapy resistance. Targeting these adipocyte-tumor interactions represents a promising approach to inhibit oncogenic signaling and restore treatment sensitivity. Disrupting this metabolic crosstalk may reprogram the tumor microenvironment, offering new combinatorial strategies for aggressive cancers like TNBC and OSCC.