ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunity

• Published in: Neoplasia (New York, N.Y.) Vol. 67; p. 101194
• Main Authors: Liu, Yiming, Jiang, Xingyu, Jing, Dongquan, Lin, Yanting, Gao, Rui, Zhao, Qixiang, Da, Huijuan, Ren, Yiming, Cao, Qiuhua, Liu, Ning, Han, Xiaoyun, Du, Juan, Gao, Xinghua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2025; Neoplasia Press; Elsevier
• Subjects: ACSL4; Animals; B7-H1 Antigen - antagonists & inhibitors; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cell Proliferation; Coenzyme A Ligases - genetics; Coenzyme A Ligases - metabolism; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Disease Models, Animal; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Long-Chain-Fatty-Acid-CoA Ligase; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Mice; Original Research; Prognosis; RIG-I-MAVS; Signal Transduction; Tumor immunity; Type I Interferon; Xenograft Model Antitumor Assays; ACSL4; Type I Interferon; Tumor immunity; Colorectal cancer; RIG-I-MAVS
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2025.101194

Background: Long-chain acyl-CoA synthetase 4 (ACSL4), a crucial modulator of ferroptosis, is associated with tumor progression, though its impact on colorectal cancer (CRC) immune dynamics is not fully understood. Methods: ACSL4 expression was analyzed in CRC tissues and correlated with patient prognosis. Effects of ACSL4 were evaluated in CRC cells in vitro and in subcutaneous and orthotopic CRC models. Flow cytometry and immunofluorescence were used to evaluate immune cell infiltration. RNA sequencing and RT-PCR were employed to identify ACSL4-regulated signaling pathways. The effect of ACSL4 silencing on PD-L1 blockade efficacy was also examined. Results: ACSL4 levels were markedly increased in CRC and linked to unfavorable patient outcomes. While ACSL4 knockdown had no direct effect on CRC cell proliferation, it significantly suppressed tumor growth in immunocompetent mice. ACSL4 depletion enhanced CD3⁺ and CD8⁺ T cell infiltration and upregulated chemokines (CXCL10, CXCL11) and antigen presentation genes (H2k1, TAP1, TAPBP). Transcriptomic analysis highlighted activation of the RIG-I-MAVS-driven type I interferon pathway. Co-culture assays demonstrated that ACSL4 knockdown promoted CD8⁺ T cell activation, and ACSL4-deficient tumors exhibited enhanced responsiveness to PD-L1 blockade. Conclusions: ACSL4 suppresses anti-tumor immunity in CRC by modulating the RIG-I-MAVS-IFN pathway, highlighting ACSL4 as a promising target for CRC immunotherapy. Effects and Mechanisms of ACSL4 Induces Immunosuppression in Colorectal Cancer ACSL4 upregulation in CRC suppresses the RIG-I-MAVS pathway, reducing IFN-β production and ISGs expression. This impairs CD8+T cell responses, including TNF-α and IFN-γ secretion, and decreases T cell chemotaxis via CXCL10 and CXCL11, contributing to immune evasion and tumor progression. [Display omitted]