Poly(I:C) and QS-21 combination suppresses breast tumor growth and metastasis by repolarizing tumor associated macrophages to anti-tumor macrophages.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by a paucity of targeted therapies, high metastatic propensity, and an immunosuppressive tumor microenvironment rich in tumor-associated macrophages (TAMs). Here, we developed a liposomal immunoadjuvant system co-encapsulating Poly(I:C) and QS-21 aimed at reprogramming TAMs and bolstering antitumor immunity. In an orthotopic 4T1 TNBC mouse model, intratumoral injection of the combined formulation markedly suppressed primary tumor growth and pulmonary metastasis, with no observable systemic toxicity. Mechanistically, the combination redirected TAMs toward an antitumor M1 phenotype, augmented antigen-presenting capacity, and promoted intratumoral infiltration of T cells and dendritic cells. Depletion of macrophages substantially abrogated the therapeutic efficacy, underscoring the pivotal role of TAMs in mediating the antitumor response. Through RNA-seq and pharmacological inhibition, we further revealed that JAK-STAT signaling is essential for macrophage inflammatory activation. Additionally, QS-21-induced lysosomal remodeling potentiated Poly(I:C) triggered TBK1-IRF3 activation and type I interferon production. Collectively, these results indicate that the liposomal Poly(I:C)/QS-21 combination holds promise as a TAM-targeted immunotherapeutic approach for TNBC.