ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunity
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 progn...
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| Format: | Article |
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Elsevier
2025-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000740 |
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| author | Yiming Liu Xingyu Jiang Dongquan Jing Yanting Lin Rui Gao Qixiang Zhao Huijuan Da Yiming Ren Qiuhua Cao Ning Liu Xiaoyun Han Juan Du Xinghua Gao |
| author_facet | Yiming Liu Xingyu Jiang Dongquan Jing Yanting Lin Rui Gao Qixiang Zhao Huijuan Da Yiming Ren Qiuhua Cao Ning Liu Xiaoyun Han Juan Du Xinghua Gao |
| author_sort | Yiming Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6ddc9bd2f0dc41ebaf2d011a8e3f02a2 |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-6ddc9bd2f0dc41ebaf2d011a8e3f02a22025-08-20T03:58:40ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-09-016710119410.1016/j.neo.2025.101194ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunityYiming Liu0Xingyu Jiang1Dongquan Jing2Yanting Lin3Rui Gao4Qixiang Zhao5Huijuan Da6Yiming Ren7Qiuhua Cao8Ning Liu9Xiaoyun Han10Juan Du11Xinghua Gao12Institute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; Translational Medicine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR ChinaInstitute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; Translational Medicine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR ChinaInstitute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; Translational Medicine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR ChinaInstitute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; Translational Medicine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR ChinaInstitute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; Translational Medicine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR ChinaInstitute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; Translational Medicine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR ChinaInstitute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; Translational Medicine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR ChinaInstitute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; Translational Medicine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR ChinaInstitute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR ChinaDepartment of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia 750001, PR ChinaDepartment of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, PR China; Co-corresponding author at: Ningxia Medical University, Ningxia, PR China. Xiaoyun Han, Shandong Cancer Hospital and Institute, Shandong, China.Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia 750001, PR China; Co-corresponding author at: Ningxia Medical University, Ningxia, PR China. Xiaoyun Han, Shandong Cancer Hospital and Institute, Shandong, China.Institute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; Translational Medicine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; Corresponding author at: China Pharmaceutical University, Nanjing, PR China.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.http://www.sciencedirect.com/science/article/pii/S1476558625000740ACSL4Tumor immunityColorectal cancerRIG-I-MAVSType I Interferon |
| spellingShingle | Yiming Liu Xingyu Jiang Dongquan Jing Yanting Lin Rui Gao Qixiang Zhao Huijuan Da Yiming Ren Qiuhua Cao Ning Liu Xiaoyun Han Juan Du Xinghua Gao ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunity Neoplasia: An International Journal for Oncology Research ACSL4 Tumor immunity Colorectal cancer RIG-I-MAVS Type I Interferon |
| title | ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunity |
| title_full | ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunity |
| title_fullStr | ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunity |
| title_full_unstemmed | ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunity |
| title_short | ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunity |
| title_sort | acsl4 knockdown inhibits colorectal cancer progression through stimulating anti tumor immunity |
| topic | ACSL4 Tumor immunity Colorectal cancer RIG-I-MAVS Type I Interferon |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000740 |
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