Abstract Background Metabolic reprogramming is a key cancer hallmark, with dysregulated fatty acid metabolism critical for tumorigenesis and progression. The acyl‐CoA synthetase long‐chain (ACSL) family (ACSL1–ACSL6) catalyzes ATP‐dependent activation of long‐chain fatty acids into acyl‐CoA, a bioactive intermediate in lipid synthesis, β‐oxidation, membrane biogenesis, and signal transduction. Dysregulated ACSL expression is widespread in malignancies, but their non‐metabolic functions (ferroptosis regulation, tumor immune microenvironment remodeling) and translational potential of targeted therapies remain to be systematically summarized. Methods This narrative review comprehensively synthesizes existing literature on the biological functions of ACSL family members in cancer. We retrieved and analyzed studies focusing on ACSL‐mediated lipid metabolic reprogramming, ferroptosis modulation, and immunomodulatory effects, with particular emphasis on isoform‐specific mechanisms and the context‐dependent roles (pro‐tumorigenic or tumor‐suppressive) of the ACSL family across different cancer types. Additionally, we summarized emerging therapeutic strategies targeting ACSL isoforms and their translational potential. Results ACSL isoforms exert distinct context‐dependent effects:ACSL1 promotes immunosuppressive TIME via M2 macrophage polarization;ACSL3/4 have antagonistic roles in ferroptosis;ACSL5 exerts dual effects via lipid metabolism, apoptosis, and immunity;ACSL6 involves autophagy and hematological malignancies. Dysregulation correlates with tumor progression, drug resistance, and immunotherapy response, while emerging ACSL‐targeted drugs show substantial translational potential. Conclusions The ACSL family serves as a key regulatory node integrating lipid metabolism, ferroptosis, and tumor immunity. Its isoform‐specific mechanisms and context‐dependent characteristics highlight its potential as a precise therapeutic target. Future research should focus on optimizing isoform‐selective inhibitors, clarifying their synergistic effects with existing therapies (e.g., immune checkpoint inhibitors, radiotherapy), and validating their translational efficacy through clinical trials to advance the development of innovative cancer treatment strategies.
Li et al. (Sun,) studied this question.