CELL INTELLIGENCE · 肿瘤细胞治疗研究

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.