CD18-targeted peptide-drug conjugate remodels the immunosuppressive tumor microenvironment of prostate cancer by selective depletion of M2 macrophages.
Peptide-drug conjugates just got a major win in prostate cancer research. Scientists engineered a new compound, TB511, that targets CD18 on M2 macrophages—the immune cells notorious for making prostate tumors harder to treat. These M2 macrophages help tumors hide from the immune system and fuel cancer growth. By designing TB511 to bind CD18 with high affinity (KD < 5 nM), researchers found a way to selectively wipe out these problem cells in the tumor microenvironment.
NPJ Precis Oncol
by Han IH, Choi I, Kim S et al.
“CD18-targeted peptide-drug conjugate remodels the immunosuppressive tumor microenvironment of prostate cancer by selective depletion of M2 macrophages. Han IH(1), Choi I(1), Kim S(2), Lee H(2), Kwon M(1), Lee WJ(1), Bae H(3). Author information: (1)Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea. (2)Twinpig Biolab Inc. R&D Center, Seoul, Republic of Korea. (3)Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea. hbae@khu.ac.kr. Castration-resistant prostate cancer (CRPC) exhibits an immunologically "cold" tumor microenvironment (TME) dominated by M2 tumor-associated macrophages (TAMs), limiting cytotoxic immune infiltration and promoting tumor progression. Targeting M2 macrophages may represent a promising therapeutic strategy. TB511 was synthesized by conjugating a TAM-specific peptide (TAMpep) to a pro-apoptotic d-form KLA peptide via a GGGGS linker. Its structure was characterized by FTIR and CD spectroscopy. Binding affinity to CD18 was determined by biolayer interferometry. A humanized prostate cancer model was established by subcutaneous implantation of PC-3 cells into hCD34+-reconstituted immunodeficient mice. TB511 exhibited high binding affinity to CD18 (KD < 5 nM), selectively induced apoptosis in M2 macrophages, and co-localized with mitochondria. In vitro, TB511 reduced macrophage viability, suppressed tumor spheroid growth, and inhibited Ki-67 and vimentin expression. In both syngeneic and humanized models, TB511 reduced tumor burden, increased M1/M2 ratio, and downregulated EMT/angiogenesis/proliferation markers. It also decreased CD8⁺ T cell exhaustion and enhanced cytotoxic CD8⁺ and NK cell activation. In vivo imaging confirmed tumor-specific accumulation and co-localization with CD206⁺/CD18⁺ cells. Collectively, CD18-targeted depletion of M2 macrophages effectively reprogrammed the immunosuppressive TME of prostate cancer, restored anti-tumor immunity, and suppressed tumor progression, supporting peptide-drug conjugates targeting M2 TAMs as potential immunotherapeutics for CRPC. © 2026. The Author(s). Conflict of interest statement: Competing interests: The authors declare no competing interests.”
Here’s what stands out from the study:
TB511 is a fusion of a TAM-specific peptide (TAMpep) and a pro-apoptotic d-form KLA peptide, linked together for precise delivery.
In humanized mouse models of castration-resistant prostate cancer, TB511 zeroed in on M2 macrophages, co-localized with mitochondria, and induced cell death—without blasting healthy cells.
The treatment shrank tumors, bumped up the ratio of anti-tumor M1 to pro-tumor M2 macrophages, and dialed down markers for cancer cell growth, angiogenesis, and EMT (epithelial-mesenchymal transition).
TB511 also recharged cytotoxic CD8+ T cells and NK cells—basically giving the immune system a green light to attack.
The big picture: This is a strong proof-of-concept for using peptide-drug conjugates to reshape the immune environment in “cold” tumors like prostate cancer. Instead of just going after cancer cells, this approach targets the cells that shield tumors from immune attack. The data suggest M2-targeted peptide conjugates could have a place in the immunotherapy toolkit for tough cancers.
For anyone tracking the future of peptide research, this is a signal that peptide-drug conjugates are more than a niche idea—they’re rapidly moving toward center stage.
Research like this keeps the peptide field exciting and full of new possibilities.
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