Abstract / Summary
Background Currently, colorectal cancer (CRC) remains a major global health challenge, with a rising incidence linked to a sedentary lifestyle and metabolic diseases, the main player being obesity (OB). Visceral adipose tissue (VAT) emerged as a key mediator of this association, functioning as a highly active endocrine-immune organ, rather than a mere energy reservoir. In OB, VAT undergoes pathological remodeling, including adipocyte hypertrophy and hypoxia, leading to a state of chronic low-grade inflammation. This review explores the mechanisms by which the dysfunctional VAT secretome orchestrates remodeling of the colorectal tumor microenvironment (TME). Main body The dysfunctional obese VAT is characterized by an imbalance in adipokine secretion (e.g., decreased adiponectin, increased leptin, and resistin), pro-inflammatory cytokines (e.g., TNF-α, IL-6, and IL-1β), and chemokines, which drive an inflammatory state. We describe the “gut-VAT-tumor axis”, illustrating how intestinal dysbiosis and increased permeability, especially for lipopolysaccharides (LPS), toxins, or short-chain fatty acids (SCFAs), trigger metabolic endotoxemia, further activating inflammatory pathways within VAT. These systemic changes remodel the colorectal TME by stimulating pathological angiogenesis, inducing epithelial-mesenchymal transition (EMT), and creating a permissive niche for immune evasion through the recruitment of immune suppressor cells. Furthermore, the role of exosomal microRNAs is highlighted as mediators of cellular crosstalk that enhance tumor aggressiveness. Also, this review analyzes emergent biomarkers identified through multi-omics, such as the systemic inflammation response index (SIRI) and specific microbiomic signatures, alongside the potential of liquid biopsy for real-time monitoring. Conclusions In conclusion, the dysfunctional VAT secretome is the central architect in remodeling the CRC TME, thereby promoting the initiation, progression, and aggressiveness of this malignancy. This aspect is making the VAT secretome a vital target for future diagnostic and targeted therapeutic strategies for obese patients with CRC.