Targeting IQGAP3 skews macrophages polarization towards M1 phenotype and promotes antitumor immune response

Immunosuppressive M2 macrophages in the tumor microenvironment (TME) limit the efficacy of immune checkpoint inhibitors (ICIs), with only ∼20% of lung adenocarcinoma (LUAD) patients benefiting from ICI monotherapy. Targeting macrophage polarization represents a promising strategy to reprogram the TME and enhance antitumor immunity.

Integrated bioinformatics analysis of TCGA and GEO datasets elucidated the role of IQGAP3 in LUAD progression. A tissue microarray was utilized to compare IQGAP3 expression between tumor and adjacent normal tissues and to evaluate the infiltration relationship between IQGAP3⁺ macrophages and CD8 + T cells. Conditioned medium (CM) from IQGAP3-knockdown macrophage was applied to evaluate its impact on LUAD cell malignancy. Subcutaneous xenograft models tested the impact of IQGAP3 targeting on tumor growth and anti-PD-1 synergy.

IQGAP3 was upregulated in LUAD and correlated with poor survival and reduced ICI benefit. IQGAP3⁺ macrophage infiltration inversely correlated with CD8 + T-cell abundance. CM from macrophage with IQGAP3 knockdown resulted in reduced proliferation, migration and invasion of LUAD cells. In macrophage-cancer cell and macrophage-CD8 + T cell coculture systems, IQGAP3 suppression enhanced macrophage phagocytosis and promoted T cell activation. Mechanistically, IQGAP3 regulates macrophage polarization through binding and sequestering IGF2BP2 at the cell periphery, thereby limiting IGF2BP2-mediated stabilization of FYN mRNA. This reduction in FYN expression led to decreased STAT1 phosphorylation. Targeting IQGAP3 reprogrammed TAMs toward an antitumor phenotype, suppressed tumor growth, and synergized with anti-PD-1 therapy.

IQGAP3 drives immunosuppressive macrophage polarization in LUAD. Its inhibition represents a novel strategy to improve immunotherapy response.