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목포대학교

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Biomaterials, May 25 2024, 310 S0142-9612(24)00159-5 | https://doi.org/10.1016/j.biomaterials.2024.122625 Immune modulation of the liver metastatic colorectal cancer microenvironment via the oral CAPOX-mediated cGAS-STING pathway

Seong Jin Park ^a, Seho Kweon ^b, Mudhibadhi Knowledge Moyo^c, Ha Rin Kim ^a,d, Jeong Uk Choi ^e, Na Kyeong Lee^f, Ruby Maharjan ^g, Young Seok Cho ^h, Jin Woo Park ^i,j, Youngro Byun ^a

^aResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea

^bCollege of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea

^cDepartment of Medicine, Boston University School of Medicine, Boston, MA, United States

^dSchool of Medicine, Oncology, Stanford University, CA, 94305, United States

^eCollege of Pharmacy, Kyung Hee University, Dongdaemun-gu, Seoul, Republic of Korea

^fCollege of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea

^gMassachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston, MA 02114, United States

^hCollege of Pharmacy, University of Michigan, Ann Arbor, MI, United States

ⁱCollege of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea

^jDepartment of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea

Corresponding authors: Jin Woo Park, Youngro Byun

Abstract

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell-mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.

논문정보

형식Research article
게재일2024년 05월 (BRIC 등록일 2024-06-05)
연구진국내 연구진
분야 생명과학 > 노화/암생물학

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