STAT6 inhibition of M2 macrophages suppresses tumor growth by modulating the tumor microenvironment in colon cancer model.

Background: Colorectal cancer (CRC) progression is strongly influenced by the tumor microenvironment (TME), where M2 tumor-associated macrophages (TAMs) establish an immunosuppressive milieu that promotes tumor growth, angiogenesis, and immune evasion. Targeting M2 TAMs has therefore emerged as a promising strategy to overcome therapeutic resistance and restore antitumor immunity. Here, we examined the effect of STAT6 modulation in M2 macrophages on reprogramming the tumor microenvironment and enhancing antitumor immune responses in colorectal cancer. Methods: We developed a peptide drug conjugate, TAMpep-IP, composed of an M2-homing peptide (TAMpep) and a STAT6-inhibitory peptide (IP), designed to selectively inhibit STAT6 signaling in M2 TAMs. The inhibitory effects of TAMpep-IP on STAT6 phosphorylation and M2-associated markers were evaluated in THP-1-derived macrophages. Antitumor efficacy of TAMpep-IP was assessed in a CT26 murine colon cancer model through analyses of tumor growth, macrophage phenotype, and T-cell activation. Results: TAMpep-IP effectively reduced STAT6 phosphorylation and downregulated M2-associated genes and proteins, including CD206, Arg-1, TGF-β, and IL-13, while upregulating the pro-inflammatory cytokine IL-1β. Conclusion: These findings demonstrate that TAMpep-IP reprograms the immunosuppressive TME by selectively suppressing STAT6 signaling in M2 TAMs, thereby restoring cytotoxic T-cell activity and inhibiting tumor progression. This selective strategy offers a promising therapeutic avenue to overcome TAM-mediated immune suppression and enhance the efficacy of existing immunotherapies.