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Cited by 49Cancer Immunotherapy and BiomarkersCancer, Lipids, and MetabolismHepatocellular Carcinoma Treatment and Prognosis

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PLT012, a Humanized CD36-Blocking Antibody, Is Effective for Unleashing Antitumor Immunity Against Liver Cancer and Liver Metastasis

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Tzeng, Sheue-Fen, Yu, Yi-Ru, Park, Jaeoh, von Renesse, Janusz, Hsiao, Huey-Wen, Hsu, Chen-Hsuan, Garnica, Josep, Chen, Jintian, Chiu, Lu-Ting, Santol, Jonas, Chen, Tse-Yu, Chung, Pei-Han, Kandalaft, Lana E., Starlinger, Patrick, Hsieh, Rodney Cheng-En, Yu, Ming-Chin, Hsiao, Pei-Wen, Carmona, Santiago J., Chen, Hung-Kai, Meng, Zhen, Lin, Yun-Han, Zhou, Jingying, Tsai, Chin-Hsien, Ho, Ping-Chih·2025·Cancer Discovery
DOI 10.1158/2159-8290.cd-24-1409PMC PMC7617665

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Abstract

Tumor cells develop various strategies to evade immune surveillance, one of which involves altering the metabolic state of the tumor microenvironment. In response to metabolic stress in the tumor microenvironment, several tumor-infiltrating immune subsets upregulate CD36 to take up lipids. This leads to impaired antitumor immunity, as intratumoral regulatory T cells exhibit increased survival and suppressive activity, whereas CD8+ T cells become more susceptible to ferroptosis and exhaustion. In this study, we develop a humanized anti-CD36 IgG4 antibody, PLT012, against the lipid-binding domain of CD36 with excellent safety and favorable pharmacokinetic features in mice and cynomolgus monkeys. PLT012 alone or in combination with PD-L1 blockade or standard-of-care immunotherapy results in robust antitumor immunity in both immunotherapy-sensitive and -resistant hepatocellular carcinomas (HCC). Notably, PLT012 also reprograms the immune landscape of human HCC ex vivo. Our findings provide proof-of-concept evidence that PLT012 reprograms antitumor immunity in HCC, positioning it as a first-in-class immunotherapy targeting CD36. Significance: Despite the success of cancer immunotherapies, like immune checkpoint inhibitors, many patients still fail to demonstrate significant responses because of metabolic constraints in tumors. PLT012 rejuvenates antitumor immunity by targeting metabolic pathways to reprogram the immune landscape of liver cancer and liver metastasis, with potential to influence future HCC immunotherapy.

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Metadata

Authors
Tzeng, S.-F., Yu, Y.-R., Park, J., von Renesse, J., Hsiao, H.-W., Hsu, C.-H., Garnica, J., Chen, J., Chiu, L.-T., Santol, J., Chen, T.-Y., Chung, P.-H., Kandalaft, L. E., Starlinger, P., Hsieh, R. C.-E., Yu, M.-C., Hsiao, P.-W., Carmona, S. J., Chen, H.-K., Meng, Z., Lin, Y.-H., Zhou, J., Tsai, C.-H., & Ho, P.-C.
Affiliations
  • Taipei Medical University (TW)
  • Ludwig Cancer Research (CH)
  • Elixiron Immunotherapeutics (Taiwan) (TW)
  • National Defense Medical Center (TW)
  • SIB Swiss Institute of Bioinformatics (CH)
  • Chinese University of Hong Kong (HK)
  • 3Pilatus Biosciences SA, Epalinges, Switzerland.
  • Sigmund Freud Privatuniversität Wien (AT)
  • Chang Gung University (TW)
  • Centre Hospitalier Universitaire Vaudois (CH)
  • Mayo Clinic (US)
  • Chang Gung Memorial Hospital (TW)
  • Agricultural Biotechnology Research Center, Academia Sinica (TW)
  • Society of Toxicology (US)
Corresponding author
  • Tsai, Chin-Hsien
  • Ho, Ping-Chih
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2025-04-28
Volume
15
Issue
8
Pages
1676-1696
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-24-1409
PMC
PMC7617665
OpenAlex
W4409883470
Cited by
49
References
11
Citations by year
2026: 39 · 2025: 10
FWCI
20.13
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cancer Discovery (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • Swiss Science National Foundation (310030L_208130, IZLCZ0_206083, CRSII5_205930, TMCG-3_213736, 205930)
  • Swiss Cancer Foundation
  • Cancer Research Institute
  • Helmut Horten Stiftung
  • National Science and Technology Council (112-2628-B-016-002, 113-2628-B-016-005, NSTC111-2314-B-182A-160-MY2, NSTC112-2628-B-182A-007-MY3, NSTC113-2314-B-182A-068)
  • Ministry of national defence-medical affair bureau (MND-MAB-D-112095)
  • Ministry of education in Taiwan (MOE-113-YSFMN-1009-001-P1)
  • National Institutes of Health (R01DK122813)
  • SFU MED Research Promotion Fund
  • Hong Kong SAR (14104820)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
anti-CD36 antibodies, CD36, lipid uptake, tumor microenvironment metabolism, hepatocellular carcinoma, liver metastasis, antitumor immunity, regulatory T cells, CD8+ T cell exhaustion, ferroptosis, PD-L1 blockade, immunotherapy resistance, humanized monoclonal antibody, cynomolgus monkey pharmacokinetics
MeSH terms
Animals, Female, Carcinoma, Hepatocellular, Humans, Immunotherapy, Liver Neoplasms, Macaca fascicularis, CD36 Antigens, Cell Line, Tumor, Mice, Tumor Microenvironment, Antibodies, Monoclonal, Humanized

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