Colon cancer remains a significant global health challenge, with inflammatory pathways such as TNF-α playing a central role in its progression. TNF-α, a key proinflammatory cytokine, is implicated in various stages of colon cancer development, including inflammation, tumor growth, and metastasis. This review provides a comprehensive overview of the molecular mechanisms through which TNF-α contributes to colon cancer progression, with a focus on its interaction with signaling pathways like NF-κB and the Wnt/β-catenin in humans. TNF-α’s involvement in promoting tumorigenesis and its complex role in the tumor microenvironment highlight its potential as both a therapeutic target and a challenge for effective treatment. This review explores the potential of anti-TNF-α therapies and the emerging role of combination strategies with immune checkpoint inhibitors. Despite promising preclinical findings, clinical application faces challenges due to the dual role of TNF-α in both promoting and inhibiting tumor progression. Future research should aim to overcome resistance mechanisms, develop personalized therapeutic strategies, and balance the effects of TNF-α in cancer therapy.

Background/Objectives: Colon cancer remains a significant health challenge world-wide, with inflammatory pathways such as tumor necrosis factor-alpha (TNF-α) playing a central role in its progression. TNF-α, a key proinflammatory cytokine, is implicated in various stages of colon cancer development, including inflammation, tumor growth, and metastasis. This review provides a comprehensive overview of the molecular mechanisms through which TNF-α contributes to colon cancer progression, with a focus on its interaction with signaling pathways like NF-κB, oxidative stress, and Wnt/β-catenin. Methods: A comprehensive review of the literature was conducted to elucidate the role of tumor necrosis factor-alpha in the pathogenesis of colon cancer. Peer-reviewed clin-ical and preclinical studies involving human subjects were identified through electronic databases, including PubMed, Scopus, and Web of Science. Selection criteria focused on studies examining the molecular mechanisms of TNF-α signaling, its interaction with key oncogenic pathways and therapeutic interventions targeting TNF-α. Data were synthesized to highlight both mechanistic insights and therapeutic applications. Results: TNF-α’s involvement in promoting tumorigenesis and its complex role in the tumor microenvironment highlight its potential as both a therapeutic target and a challenge for effective treatment. The review also delves into the potential of an-ti-TNF-α therapies and the emerging role of combination strategies with immune checkpoint inhibitors. Despite promising preclinical findings, clinical application faces challenges due to the dual role of TNF-α in both promoting and inhibiting tumor pro-gression. Conclusion: Future research should focus on overcoming resistance mechanisms, de-veloping personalized therapeutic strategies, and balancing the effects of TNF-α in cancer therapy.