Selective targeting of M2-like tumor-associated macrophages by TB511 promotes NK cell-associated antitumor immunity in prostate cancer

Prostate cancer progression is strongly influenced by the tumor immune microenvironment, in which M2-like tumor-associated macrophages (TAMs) promote immune suppression and tumor growth. Although TAM-targeted therapies have emerged as promising immunomodulatory strategies, the downstream immune effector mechanisms associated with tumor suppression after M2-like TAM targeting remain incompletely defined. Here, we investigated whether TB511, an M2-like TAM-targeting peptide-drug conjugate, suppresses prostate tumor growth by remodeling the M2-like TAM compartment and promoting NK cell-associated antitumor immunity. TIMER3.0 analysis of human prostate adenocarcinoma datasets showed increased expression of M2-like TAM-associated genes and reduced expression of several NK cell-associated genes in tumor tissues compared with normal prostate tissues. In immunocompetent TRAMP-C2 and RM-1 syngeneic prostate cancer models, TB511 significantly reduced tumor growth and tumor burden. TB511 selectively decreased F4/80 + CD206 + M2-like macrophages without significantly reducing F4/80 + CD86 + M1-like macrophages, increased the M1/M2 macrophage ratio, and suppressed M2-associated immunosuppressive genes, including ARG1, CD163, TGFB, and IL10. TB511 also increased CD8 + T-cell and NK cell infiltration, enhanced NCR1-positive cells, increased GZMB-expressing NK-associated cytotoxic cells, increased NK-associated effector genes, and decreased the inhibitory receptor-associated genes NKG2A and TIGIT. In contrast, TB511 failed to suppress TRAMP-C2 tumor growth in immunodeficient NSG mice, supporting an immune-dependent component of its antitumor activity. Immune cell depletion experiments further revealed that CD8 T-cell depletion did not abolish TB511-mediated tumor suppression, whereas NK1.1 + cell depletion eliminated the antitumor effect of TB511. Notably, TB511 still reduced M2-like macrophages under NK1.1 + cell-depleted conditions, indicating that macrophage remodeling alone is insufficient for tumor control without NK1.1 + cells. These findings demonstrate that TB511 suppresses prostate tumor growth by selectively reducing M2-like TAMs and promoting NK cell-associated cytotoxic antitumor immunity, with NK1.1 + cells required for therapeutic efficacy. TB511 may represent a promising immunomodulatory peptide-drug conjugate for targeting the M2-like TAM-NK cell axis in prostate cancer.