Reprogramming tumor-associated macrophages using STING or TLR agonists: a promising strategy to enhance immunotherapy in hormone-dependent cancers.

Hormone-dependent cancers, like breast and prostate cancers, represent a unique challenge in oncology due to their complex interplay between hormone signaling, immune evasion, and therapeutic resistance. While endocrine therapies effectively target hormone signaling to initially control disease, resistance mechanisms frequently emerge, leading to cancer progression and limited survival. These solid tumors further complicate treatment by establishing an immunosuppressive tumor microenvironment (TME), presenting variable numbers of immune cells depending on cancer type and stage, which hinders the efficacy of immune checkpoint inhibitors. In this TME, tumor-associated macrophages (TAMs) are the major cellular source of immunosuppression, supporting tumor growth. The ability of TAMs to hamper the effectiveness of endocrine therapy is becoming increasingly recognized. Reprogramming TAMs within solid tumors can restore their natural ability to fight cancer and also enhance antitumoral efficacy. In this line of research, Al-Janabi have recently developed lipid nanoparticles decorated with antibodies that bind to the folate receptor-beta overexpressed in perivascular TAMs and loaded with a STING agonist (cGAMP) for the reprogramming of these TAMs. In preclinical murine models of prostate cancer, this therapeutic approach demonstrated significant synergistic activity with androgen deprivation therapy. This work provides an excellent example of TAM reprogramming combined with endocrine therapy for the treatment of hormone-dependent cancers.