biostudies-literatureTzeng SFCancer Research Institute (CRI)Swiss Cancer Foundation (SCF)Swiss Science National FoundationMinistry of national defence-medical affair bureauNational Institutes of Health (NIH)National Science and Technology Councilswiss science national foundationNational Institutes of HealthCancer Research InstituteHelmut Horten Stiftung (Helmut Horten Foundation)Helmut Horten StiftungSwiss Cancer FoundationSwiss National Science FoundationNIDDK NIH HHSSFU MED Research Promotion FundHong Kong SARMinistry of education in TaiwanNational Science and Technology Council (NSTC)1676-1696https://www.ebi.ac.uk/biostudies/studies/S-EPMC7617665biostudies-literatureUnknown15(8)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.<h4>Significance</h4>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.Cancer discoveryPLT012, a Humanized CD36-Blocking Antibody, Is Effective for Unleashing Antitumor Immunity Against Liver Cancer and Liver Metastasis.PMC7617665R01 DK122813112-2628-B-016-002IZLCZ0_206083163204310030L_208130CRSII5_20593020593014104820MOE-113-YSFMN-1009-001-P1TMCG-3_213736NSTC111-2314-B-182A-160-MY2NSTC113-2314-B-182A-068R01DK122813NSTC112-2628-B-182A-007-MY3113-2628-B-016-005MND-MAB-D-112095Chiu LTStarlinger PYu MCPark JGarnica JChen JHo PCYu YRvon Renesse JKandalaft LETzeng SFChen TYHsiao PWMeng ZChen HKTsai CHSantol JHsiao HWChung PHLin YHCarmona SJHsu CHHsieh RCZhou JfalsePLT012, a Humanized CD36-Blocking Antibody, Is Effective for Unleashing Antitumor Immunity Against Liver Cancer and Liver Metastasis.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.<h4>Significance</h4>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.2025-01-01T00:00:00Z2025 Aug2026-05-31T03:08:27.746Z2026-05-31T03:07:34.224ZS-EPMC76176654029402210.1158/2159-8290.cd-24-140910.1158/2159-8290.CD-24-1409