2. Academic Validation
  3. Immune modulation of the liver metastatic colorectal cancer microenvironment via the oral CAPOX-mediated cGAS-STING pathway

Immune modulation of the liver metastatic colorectal cancer microenvironment via the oral CAPOX-mediated cGAS-STING pathway

  • Biomaterials. 2024 Oct:310:122625. doi: 10.1016/j.biomaterials.2024.122625.
Seong Jin Park 1,  Seho Kweon 2,  Mudhibadhi Knowledge Moyo 3,  Ha Rin Kim 4,  Jeong Uk Choi 5,  Na Kyeong Lee 6,  Ruby Maharjan 7,  Young Seok Cho 8,  Jin Woo Park 9,  Youngro Byun 10
Affiliations

Affiliations

  • 1 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.
  • 3 Department of Medicine, Boston University School of Medicine, Boston, MA, United States.
  • 4 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; School of Medicine, Oncology, Stanford University, CA, 94305, United States.
  • 5 College of Pharmacy, Kyung Hee University, Dongdaemun-gu, Seoul, Republic of Korea.
  • 6 College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea.
  • 7 Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston, MA 02114, United States.
  • 8 College of Pharmacy, University of Michigan, Ann Arbor, MI, United States.
  • 9 College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea; Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea. Electronic address: jwpark@mokpo.ac.kr.
  • 10 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: yrbyun@snu.ac.kr.
PMID: 38820768 DOI: 10.1016/j.biomaterials.2024.122625
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.

Keywords

Capecitabine; Chemo-immunotherapy; Liver metastatic tumor; Nano-micelle; Oral metronomic CAPOX; Oxaliplatin; STING activation.

Figures
Products