Autophagy in cancer-associated fibroblasts: its role in gastrointestinal cancers

Gastrointestinal (GI) cancers are a heterogeneous group of cancers with high morbidity and mortality rates. Despite advancements in early detection markers and therapy, the outcome remains poor due to high tumor heterogeneity and metastasis. The microenvironment (ME) in GI cancers is highly dynamic and enriched with immune and endothelial cells, extracellular matrix (ECM), and stromal components, including cancer associated fibroblasts (CAFs), which play an essential role in tumor progression. CAFs modulate tumor progression through extensive crosstalk with cancer cells, immune cells, and ECM remodeling. CAFs secrete cytokines, growth factors, and exosomes that modulate tumor progression, epithelial to mesenchymal transition, angiogenesis, immune tolerance, and therapy resistance. By remodeling the ECM, CAFs create a protumorgenic microenvironment through the activation of key signaling pathways such as YAP/TAZ and integrin/FAK. CAFs are also heterogeneous, with diverse subsets exhibiting context-dependent pro- or anti-tumor function, as discussed in this review. Autophagy is a process that removes damaged cellular components to maintain homeostasis. In the early stage of cancer, autophagy suppresses tumor progression. Still, in the later stages of tumors, CAFs support survival, metabolic alterations, therapy resistance, and immune evasion, as such are regulated by signals like TGF-β/IL-6/ROS and pathways including AMPK/STAT3/NF-κB/SMAD and mTOR. The review discusses CAFs and modulation of autophagy in GI cancer progression, metastasis, and resistance to therapy. CAFs remodel the ME and induce immune tolerance, while autophagy in both cancer cells and CAFs allows survival under stress. By showing these interconnected mechanisms, the review identifies CAF autophagy as a critical therapeutic target to overcome resistance in GI cancers.