Overcoming Anti-PD-1 Resistance: Targeted STING Activation Reprograms Tumor-Associated Macrophages
DOI:
https://doi.org/10.63808/ghc.v2i1.540Keywords:
Anti-PD-1 resistance, STING, Tumor-associated macrophages, Immune reprogramming, Tumor microenvironmentAbstract
Anti-PD-1 immunotherapy has limited response rates in various solid tumors, and the immunosuppressive microenvironment mediated by tumor-associated macrophages (TAMs) is a key factor leading to resistance. This study aims to explore whether targeting and activating the STING pathway can reprogram TAMs to reverse resistance to anti-PD-1 therapy. An anti-PD-1 resistant mouse transplant tumor model was established, and intratumoral injection or nanoparticle-targeted delivery of a STING agonist was used. Flow cytometry, multiplex immunohistochemistry, transcriptome sequencing, and other methods were employed to analyze TAM polarization phenotypes, cytokine expression, and tumor-infiltrating lymphocyte function, as well as to systematically evaluate the antitumor effect of STING agonist combined with anti-PD-1 therapy. STING activation significantly promoted the conversion of TAMs from an immunosuppressive M2 phenotype to a pro-inflammatory M1 phenotype, upregulated the expression of MHC-II, CD86, and type I interferon-related genes, and enhanced antigen-presenting capability; at the same time, it remodeled the tumor microenvironment, increased CD8 T cell infiltration and granzyme B and IFN-γ secretion, and reduced the proportion of regulatory T cells. In the resistant model, STING agonist combined with anti-PD-1 therapy significantly inhibited tumor growth and prolonged mouse survival compared with monotherapy, with some mice achieving complete tumor regression. Targeting the STING pathway can reprogram TAMs to remodel the tumor immune microenvironment and effectively overcome resistance to anti-PD-1 therapy, providing a new strategy for clinical combination immunotherapy.
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