{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T08:01:47Z","timestamp":1780128107513,"version":"3.54.0"},"reference-count":31,"publisher":"IMR Press","issue":"5","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Colorectal cancer (CRC) progression is frequently driven by metabolic reprogramming and immune evasion. A crucial metabolic enzyme, argininosuccinate synthetase 1 (ASS1), is dysregulated in a number of malignancies; however, its role in CRC and its effects on the tumor immune microenvironment remain poorly understood. Carnitine palmitoyltransferase 1A (CPT1A)-mediated fatty acid oxidation and post-translational modifications, including succinylation, are emerging as important regulators of tumor behavior. Methods: ASS1 expression was analyzed using The Cancer Genome Atlas (TCGA) database and further validated in 40 paired clinical CRC specimens and cell lines. Functional roles were assessed through knockdown and overexpression experiments in CRC cells, evaluating proliferation, colony formation, migration, and invasion. Mechanisms were explored via co-immunoprecipitation, succinylation assays, protein stability measurements, and co-culture systems with CD8+ T cells. Additionally, in vivo tumor growth and changes in the immune milieu were evaluated using a mouse CT26 transplantation model. Results: ASS1 was markedly upregulation in both cultured cell lines and CRC tissues. ASS1 knockdown decreased programmed cell death protein-1 (PD-1) expression and T cell fatigue while enhancing interferon-\u03b3, tumor necrosis factor-\u03b1, perforin, and granzyme B secretion, which in turn increased CD8+ T cell cytotoxicity and inhibited malignant phenotypes in vitro. Mechanistically, ASS1 transcriptionally activated CPT1A, which promoted S100 calcium-binding protein A10 (S100A10) succinylation at lysine 47, thereby stabilizing S100A10 protein. Overexpression of either CPT1A or S100A10 reversed the tumor growth suppression and impaired immune activation resulting from ASS1 knockdown. In vivo, ASS1 knockdown inhibited tumor growth, downregulated CPT1A and S100A10 expression, and increased CD8+ T cell infiltration while reducing PD-1 levels. Conclusions: ASS1 promotes CRC progression and immune escape by regulating the CPT1A-mediated succinylation and stabilization of S100A10. These findings highlight the ASS1\/CPT1A\/S100A10 axis as a potential therapeutic target for CRC.<\/jats:p>","DOI":"10.31083\/fbl48764","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T07:25:36Z","timestamp":1780125936000},"source":"Crossref","is-referenced-by-count":0,"title":["ASS1 Promotes Colorectal Cancer Immune Evasion Through CPT1A-Mediated S100A10 Succinylation"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7543-9231","authenticated-orcid":true,"given":"Liping","family":"Sun","sequence":"first","affiliation":[{"name":"Interventional Oncology Department, Central Hospital of Zibo, 255000 Zibo, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2706-5538","authenticated-orcid":true,"given":"Daidi","family":"Fu","sequence":"additional","affiliation":[{"name":"Oncology Department of West Hospital, Central Hospital of Zibo, 255000 Zibo, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5598-5947","authenticated-orcid":true,"given":"Heng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Oncology Department of West Hospital, Central Hospital of Zibo, 255000 Zibo, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019; 394: 1467\u20131480.","DOI":"10.1016\/S0140-6736(19)32319-0"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Abedizadeh R, Majidi F, Khorasani HR, Abedi H, Sabour D. Colorectal cancer: a comprehensive review of carcinogenesis, diagnosis, and novel strategies for classified treatments. Cancer Metastasis Reviews. 2024; 43: 729\u2013753.","DOI":"10.1007\/s10555-023-10158-3"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Jin K, Ren C, Liu Y, Lan H, Wang Z. An update on colorectal cancer microenvironment, epigenetic and immunotherapy. International Journal of Molecular Sciences. 2020; 89: 107041.","DOI":"10.1016\/j.intimp.2020.107041"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. International Journal of Molecular Sciences. 2024; 25: 9463.","DOI":"10.3390\/ijms25179463"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Huang HY, Wu WR, Wang YH, Wang JW, Fang FM, Tsai JW, et al. ASS1 as a novel tumor suppressor gene in myxofibrosarcomas: aberrant loss via epigenetic DNA methylation confers aggressive phenotypes, negative prognostic impact, and therapeutic relevance. Clinical Cancer Research. 2013; 19: 2861\u20132872.","DOI":"10.1158\/1078-0432.CCR-12-2641"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Long Y, Tsai WB, Wang D, Hawke DH, Savaraj N, Feun LG, et al. Argininosuccinate synthetase 1 (ASS1) is a common metabolic marker of chemosensitivity for targeted arginine- and glutamine-starvation therapy. Cancer Letters. 2017; 388: 54\u201363.","DOI":"10.1016\/j.canlet.2016.11.028"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Luo W, Zou Z, Nie Y, Luo J, Ming Z, Hu X, et al. ASS1 inhibits triple-negative breast cancer by regulating PHGDH stability and de novo serine synthesis. Cell Death & Disease. 2024; 15: 319.","DOI":"10.1038\/s41419-024-06672-z"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Du D, Liu C, Qin M, Zhang X, Xi T, Yuan S, et al. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma. Acta Pharmaceutica Sinica. B. 2022; 12: 558\u2013580.","DOI":"10.1016\/j.apsb.2021.09.019"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Fu Y, Liu S, Rodrigues RM, Han Y, Guo C, Zhu Z, et al. Activation of VIPR1 suppresses hepatocellular carcinoma progression by regulating arginine and pyrimidine metabolism. International Journal of Biological Sciences. 2022; 18: 4341\u20134356.","DOI":"10.7150\/ijbs.71134"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Madiraju AK, Alves T, Zhao X, Cline GW, Zhang D, Bhanot S, et al. Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism. Proceedings of the National Academy of Sciences of the United States of America. 2016; 113: E3423\u2013E3430.","DOI":"10.1073\/pnas.1606022113"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Hu Q, Dai J, Zhang Z, Yu H, Zhang J, Zhu X, et al. ASS1-Mediated Reductive Carboxylation of Cytosolic Glutamine Confers Ferroptosis Resistance in Cancer Cells. Cancer Research. 2023; 83: 1646\u20131665.","DOI":"10.1158\/0008-5472.CAN-22-1999"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Gai X, Liu Y, Lan X, Chen L, Yuan T, Xu J, et al. Oncogenic KRAS Induces Arginine Auxotrophy and Confers a Therapeutic Vulnerability to SLC7A1 Inhibition in Non-Small Cell Lung Cancer. Cancer Research. 2024; 84: 1963\u20131977.","DOI":"10.1158\/0008-5472.CAN-23-2095"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Cheng C, Geng F, Cheng X, Guo D. Lipid metabolism reprogramming and its potential targets in cancer. Cancer Communications. 2018; 38: 27.","DOI":"10.1186\/s40880-018-0301-4"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Schlaepfer IR, Joshi M. CPT1A-mediated Fat Oxidation, Mechanisms, and Therapeutic Potential. Endocrinology. 2020; 161: bqz046.","DOI":"10.1210\/endocr\/bqz046"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Wang YN, Zeng ZL, Lu J, Wang Y, Liu ZX, He MM, et al. CPT1A-mediated fatty acid oxidation promotes colorectal cancer cell metastasis by inhibiting anoikis. Oncogene. 2018; 37: 6025\u20136040.","DOI":"10.1038\/s41388-018-0384-z"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Wang X, Huang H, Sze KMF, Wang J, Tian L, Lu J, et al. S100A10 promotes HCC development and progression via transfer in extracellular vesicles and regulating their protein cargos. Gut. 2023; 72: 1370\u20131384.","DOI":"10.1136\/gutjnl-2022-327998"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Li J, Zhou C, Gao X, Tan T, Zhang M, Li Y, et al. S100A10 promotes cancer metastasis via recruitment of MDSCs within the lungs. Oncoimmunology. 2024; 13: 2381803.","DOI":"10.1080\/2162402X.2024.2381803"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Liu Z, Wang R, Wang Y, Duan Y, Zhan H. Targeting succinylation-mediated metabolic reprogramming as a potential approach for cancer therapy. Biomedicine & Pharmacotherapy. 2023; 168: 115713.","DOI":"10.1016\/j.biopha.2023.115713"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Chen C, Zhao F, Peng J, Zhao D, Xu L, Li H, et al. Soluble Tim-3 serves as a tumor prognostic marker and therapeutic target for CD8+ T cell exhaustion and anti-PD-1 resistance. Cell Reports. Medicine. 2024; 5: 101686.","DOI":"10.1016\/j.xcrm.2024.101686"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Wang H, Tian T, Zhang J. Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): From Mechanism to Therapy and Prognosis. International Journal of Molecular Sciences. 2021; 22: 8470.","DOI":"10.3390\/ijms22168470"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Lee JS, Adler L, Karathia H, Carmel N, Rabinovich S, Auslander N, et al. Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures. Cell. 2018; 174: 1559\u20131570.e22.","DOI":"10.1016\/j.cell.2018.07.019"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Sawyer BT, Qamar L, Yamamoto TM, McMellen A, Watson ZL, Richer JK, et al. Targeting Fatty Acid Oxidation to Promote Anoikis and Inhibit Ovarian Cancer Progression. Molecular Cancer Research. 2020; 18: 1088\u20131098.","DOI":"10.1158\/1541-7786.MCR-19-1057"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Delage B, Fennell DA, Nicholson L, McNeish I, Lemoine NR, Crook T, et al. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. International Journal of Cancer. 2010; 126: 2762\u20132772.","DOI":"10.1002\/ijc.25202"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Bateman LA, Ku WM, Heslin MJ, Contreras CM, Skibola CF, Nomura DK. Argininosuccinate Synthase 1 is a Metabolic Regulator of Colorectal Cancer Pathogenicity. ACS Chemical Biology. 2017; 12: 905\u2013911.","DOI":"10.1021\/acschembio.6b01158"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Kurmi K, Hitosugi S, Wiese EK, Boakye-Agyeman F, Gonsalves WI, Lou Z, et al. Carnitine Palmitoyltransferase 1A Has a Lysine Succinyltransferase Activity. Cell Reports. 2018; 22: 1365\u20131373.","DOI":"10.1016\/j.celrep.2018.01.030"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Li X, Zhang C, Zhao T, Su Z, Li M, Hu J, et al. Lysine-222 succinylation reduces lysosomal degradation of lactate dehydrogenase a and is increased in gastric cancer. Journal of Experimental & Clinical Cancer Research. 2020; 39: 172.","DOI":"10.1186\/s13046-020-01681-0"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Wang C, Zhang C, Li X, Shen J, Xu Y, Shi H, et al. CPT1A-mediated succinylation of S100A10 increases human gastric cancer invasion. Journal of Cellular and Molecular Medicine. 2019; 23: 293\u2013305.","DOI":"10.1111\/jcmm.13920"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Noye TM, Lokman NA, Oehler MK, Ricciardelli C. S100A10 and Cancer Hallmarks: Structure, Functions, and its Emerging Role in Ovarian Cancer. International Journal of Molecular Sciences. 2018; 19: 4122.","DOI":"10.3390\/ijms19124122"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Lin H, Yang P, Li B, Chang Y, Chen Y, Li Y, et al. S100A10 Promotes Pancreatic Ductal Adenocarcinoma Cells Proliferation, Migration and Adhesion through JNK\/LAMB3-LAMC2 Axis. Cancers. 2022; 15: 202.","DOI":"10.3390\/cancers15010202"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Okura GC, Bharadwaj AG, Waisman DM. Recent Advances in Molecular and Cellular Functions of S100A10. Biomolecules. 2023; 13: 1450.","DOI":"10.3390\/biom13101450"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Svenningsson P, Greengard P. p11 (S100A10)\u2013an inducible adaptor protein that modulates neuronal functions. Current Opinion in Pharmacology. 2007; 7: 27\u201332.","DOI":"10.1016\/j.coph.2006.10.001"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/5\/10.31083\/FBL48764","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T07:26:28Z","timestamp":1780125988000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/5\/10.31083\/FBL48764"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":31,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026]]}},"alternative-id":["S2768-6701(26)02065-4"],"URL":"https:\/\/doi.org\/10.31083\/fbl48764","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,18]]},"article-number":"48764"}}