TAMpep-IP, a STAT6-inhibitory peptide conjugate, suppresses colon tumor growth by reprogramming M2 macrophages.

Colorectal cancer (CRC) progression is heavily influenced by the tumor microenvironment (TME), where M2 tumor-associated macrophages (TAMs) foster an immunosuppressive milieu, promoting tumor growth, angiogenesis, and immune evasion. Current therapies often face resistance due to this suppressive environment. Targeting M2 TAMs offers a promising strategy to overcome resistance and restore antitumor immunity. This study investigates STAT6 modulation in M2 macrophages to reprogram the TME and enhance antitumor responses in CRC.

Researchers developed TAMpep-IP, a peptide drug conjugate comprising an M2-homing peptide (TAMpep) and a STAT6-inhibitory peptide (IP), designed for selective STAT6 inhibition in M2 TAMs. In vitro, they assessed its inhibitory effects on STAT6 phosphorylation and M2-associated markers in THP-1-derived macrophages. Antitumor efficacy was then evaluated in a CT26 murine colon cancer model, analyzing tumor growth, macrophage phenotype, and T-cell activation. The study compared TAMpep-IP treatment against an implied untreated control arm.

In vitro, TAMpep-IP effectively reduced STAT6 phosphorylation and significantly downregulated M2-associated genes and proteins, including CD206, Arg-1, TGF-β, and IL-13, while simultaneously upregulating the pro-inflammatory cytokine IL-1β. In vivo, TAMpep-IP treatment significantly suppressed tumor growth and proliferation, accompanied by a marked reduction of M2-like TAM infiltration and decreased TGFB expression in tumor tissues. Importantly, TAMpep-IP enhanced antitumor immunity by increasing the population of Granzyme B+ CD8+ T cells and reducing PD-1+ and TIM-3+ exhausted CD8+ T cells. This was further supported by elevated levels of TNF-α, IL-1β, and IL-12 within the tumor microenvironment, indicating a shift towards a more immunostimulatory TME.