Unraveling the intricacies of cancer-associated fibroblasts: a comprehensive review on metabolic reprogramming and tumor microenvironment crosstalk

Abstract

Cancer-associated fibroblasts (CAFs) are crucial component of tumor microenvironment (TME) which undergo significant phenotypic changes and metabolic reprogramming, profoundly impacting tumor growth. This review delves into CAF plasticity, diverse origins, and the molecular mechanisms driving their continuous activation. Emphasis is placed on the intricate bidirectional crosstalk between CAFs and tumor cells, promoting cancer cell survival, proliferation, invasion, and immune evasion. Metabolic reprogramming, a cancer hallmark, extends beyond cancer cells to CAFs, contributing to the complex metabolic interplay within the TME. The 'reverse Warburg effect' in CAFs mirrors the Warburg effect, involving the export of high-energy substrates to fuel cancer cells, supporting their rapid proliferation. Molecular regulations by key players like p53, Myc, and K-RAS orchestrate this metabolic adaptation. Understanding the metabolic symbiosis between CAFs and tumor cells opens avenues for targeted therapeutic strategies to disrupt this dynamic crosstalk. Unraveling CAF-mediated metabolic reprogramming provides valuable insights for developing novel anticancer therapies. This comprehensive review consolidates current knowledge, shedding light on CAFs' multifaceted roles in the TME and offering potential targets for future therapies.

Keywords: Tumor microenvironment; Warburg effect; cancer‐associated fibroblasts; metabolic reprogramming.