Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation
Abstract Immunotherapy including anti-PD-1 demonstrated therapeutic promise to colorectal cancer (CRC) patients, but tumor cell resistance limits their efficacy. Butyrate may influence therapeutic outcomes by modulating tumor metabolism, but it remains unclear whether butyrate influences CRC cell re...
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Springer
2025-05-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-025-02686-x |
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| author | Ran Zhu Shujiang Gu Yuan Tao Yan Zhang |
| author_facet | Ran Zhu Shujiang Gu Yuan Tao Yan Zhang |
| author_sort | Ran Zhu |
| collection | DOAJ |
| description | Abstract Immunotherapy including anti-PD-1 demonstrated therapeutic promise to colorectal cancer (CRC) patients, but tumor cell resistance limits their efficacy. Butyrate may influence therapeutic outcomes by modulating tumor metabolism, but it remains unclear whether butyrate influences CRC cell resistance to anti-PD-1 therapy. We aimed to investigate whether butyrate promotes resistance to anti-PD-1 therapy in CRC and underlying metabolic and immunologic mechanisms. CRC murine models were established by subcutaneously inoculating MC38 cells or butyrate/anti-PD-1-administered tumor cells of mice, followed by treatment with butyrate, anti-PD-1, or a combination. Therapeutic efficacy was assessed by tumor growth and survival outcomes. In vitro, HCT116 cells were exposed to monotherapy or co-therapy regimens. Carnitine Palmitoyltransferase 1A (CPT1A) knockdown was conducted by shRNA transfection both in vivo and in vitro. Fatty acid oxidation (FAO) was determined by oxygen consumption rate and CPT1A expression. CD8+ T cell cytotoxicity assays and CD8 expression in tumors were performed to evaluate immune cell infiltration. The addition of butyrate into anti-PD-1 treatment combination did not improve survival or reduce tumor volume compared to anti-PD-1 alone, with a marked activation of CPT1A observed in treated tumor tissues. Butyrate significantly elevated FAO, contributing to elevated oxygen consumption rate and reduced CD8+ T cell cytotoxicity. However, in sh-CPT1A models, the combination therapy significantly improved antitumor efficacy and restored CD8+ T cell infiltration. Furthermore, CRC patient samples resistant to anti-PD-1 therapy exhibited elevated CPT1A levels. Butyrate-induced CPT1A-mediated FAO promotes resistance to anti-PD-1 therapy in CRC, suggesting that targeting CPT1A might enhance the efficacy of immunotherapy. |
| format | Article |
| id | doaj-art-cac73cb2ddaf4f4991325c075485430e |
| institution | OA Journals |
| issn | 2730-6011 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj-art-cac73cb2ddaf4f4991325c075485430e2025-08-20T01:59:57ZengSpringerDiscover Oncology2730-60112025-05-0116111310.1007/s12672-025-02686-xButyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidationRan Zhu0Shujiang Gu1Yuan Tao2Yan Zhang3Department of Pathology, Changping Hospital of Integrated Chinese and Western MedicineDepartment of Laboratory Medicine, Beijing Changping Traditional Chinese Medicine HospitalDepartment of Gastroenterology, Beijing Changping Traditional Chinese Medicine HospitalDepartment of Pathology, Beijing Changping Traditional Chinese Medicine HospitalAbstract Immunotherapy including anti-PD-1 demonstrated therapeutic promise to colorectal cancer (CRC) patients, but tumor cell resistance limits their efficacy. Butyrate may influence therapeutic outcomes by modulating tumor metabolism, but it remains unclear whether butyrate influences CRC cell resistance to anti-PD-1 therapy. We aimed to investigate whether butyrate promotes resistance to anti-PD-1 therapy in CRC and underlying metabolic and immunologic mechanisms. CRC murine models were established by subcutaneously inoculating MC38 cells or butyrate/anti-PD-1-administered tumor cells of mice, followed by treatment with butyrate, anti-PD-1, or a combination. Therapeutic efficacy was assessed by tumor growth and survival outcomes. In vitro, HCT116 cells were exposed to monotherapy or co-therapy regimens. Carnitine Palmitoyltransferase 1A (CPT1A) knockdown was conducted by shRNA transfection both in vivo and in vitro. Fatty acid oxidation (FAO) was determined by oxygen consumption rate and CPT1A expression. CD8+ T cell cytotoxicity assays and CD8 expression in tumors were performed to evaluate immune cell infiltration. The addition of butyrate into anti-PD-1 treatment combination did not improve survival or reduce tumor volume compared to anti-PD-1 alone, with a marked activation of CPT1A observed in treated tumor tissues. Butyrate significantly elevated FAO, contributing to elevated oxygen consumption rate and reduced CD8+ T cell cytotoxicity. However, in sh-CPT1A models, the combination therapy significantly improved antitumor efficacy and restored CD8+ T cell infiltration. Furthermore, CRC patient samples resistant to anti-PD-1 therapy exhibited elevated CPT1A levels. Butyrate-induced CPT1A-mediated FAO promotes resistance to anti-PD-1 therapy in CRC, suggesting that targeting CPT1A might enhance the efficacy of immunotherapy.https://doi.org/10.1007/s12672-025-02686-xButyrateCPT1AColorectal cancerFatty acid oxidationImmune resistanceAnti-PD-1 therapy |
| spellingShingle | Ran Zhu Shujiang Gu Yuan Tao Yan Zhang Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation Discover Oncology Butyrate CPT1A Colorectal cancer Fatty acid oxidation Immune resistance Anti-PD-1 therapy |
| title | Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation |
| title_full | Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation |
| title_fullStr | Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation |
| title_full_unstemmed | Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation |
| title_short | Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation |
| title_sort | butyrate confers colorectal cancer cell resistance to anti pd 1 therapy by promoting cpt1a mediated fatty acid oxidation |
| topic | Butyrate CPT1A Colorectal cancer Fatty acid oxidation Immune resistance Anti-PD-1 therapy |
| url | https://doi.org/10.1007/s12672-025-02686-x |
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