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

Sep 23, 2026

Uploaded by Stanley

Hormone-dependent cancers such as breast and prostate cancer present a dual challenge: hormone-driven tumor growth and immune escape that limits durable responses. Endocrine therapy can initially control disease, but resistance emerges and reshapes the tumor microenvironment (TME) into an immunosuppressive state. Tumor-associated macrophages (TAMs) become a dominant source of immunosuppression, enabling tumor progression and reducing checkpoint inhibitor effectiveness. Reprogramming TAMs aims to restore anti-tumor activity and improve endocrine synergy, exemplified by STING agonist-loaded, antibody-decorated lipid nanoparticles.

LanguageEnglish

CategoryHealthcare

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Pages4

Reading Time10 min

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Abstract

Hormone-dependent cancers and endocrine resistance

Immunosuppressive tumor microenvironment (TME)

Role of tumor-associated macrophages (TAMs)

TAM reprogramming with STING or TLR agonists

Open access Commentary Reprogramming tumor-associated macrophages using STING or TLRagonists: a promising strategy to enhance immunotherapy in hormonedependent cancers Victor Sacristan Santos ,1,2 Alba Pensado-López,1,2 Rosario García-Campelo,1,2 Silvia Antolin Novoa,1,2 Rosa Señaris Rodriguez,3 Fernando Torres Andón 1,2 To cite: Sacristan Santos V, Pensado-López A, García-Campelo R, et al. Reprogramming tumorassociated macrophages using STING or TLR agonists: a promising strategy to enhance immunotherapy in hormonedependent cancers. Journal for ImmunoTherapy of Cancer 2025;13:e010950 . doi:10 . 1136/ jitc-2024-010950 Accepted 06 May 2025 © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group. 1Medical Oncology Department, INIBIC, A Coruna, Galicia, Spain 2Complexo Hospitalario Universitario A Coruña, ACoruna, Galicia, Spain 3Department of Physiology, Centro de Investigaciónen Medicina Molecular y Enfermedades Crónicas (CiMUS), Universidade de Santiago de CompostelaCampus de Santiago, Santiago de Compostela, Spain Correspondence to Dr Fernando Torres Andón; fernando.torres.andon@sergas. es ABSTRACT 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 etal have recently developed lipid nanoparticles decorated with antibodies that bind to the folate receptorbeta 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. Hormone-dependent cancers encompass a significant subset of tumors, with breast cancer (BC) being the most prevalent in women and prostate cancer (PC) in men. Other common hormone-dependent cancers in women include ovarian and endometrial cancer. Sex steroid hormones, such as estrogen and androgen, stimulate the progression and malignancy of cancer cells in luminal breast and prostate tumors. These hormones act through dedicated receptors, primarily expressed in the nucleus, that are overexpressed in cancer cells. Thus, a broad spectrum of therapeutic approaches, known as endocrine therapies, has been developed to block or inhibit the estrogen receptors (ER) in BC or the androgen receptors (AR) in PC, or other mechanisms along their respective hormone signaling pathways. Current treatments in clinical oncology involve endocrine therapies, but also surgery and cytotoxic drugs or cell cycle inhibitors. With the combination of these therapeutic approaches, median survival rates of approximately 5 years can be achieved in metastatic hormone-dependent tumors, with complete response rates of ~40% in localized BC and ~65% in localized PC.1 2 In PC, androgen deprivation therapy (ADT) is the foundation of the most effective treatments. Althoug

FAQs

Why are immune checkpoint inhibitors less effective in hormone-dependent breast and prostate cancers?

The immunosuppressive tumor microenvironment limits immune cell effectiveness, and hormone-dependent tumors are often described as “cold” with reduced infiltration. Tumor-associated macrophages (TAMs) are a key source of immunosuppression that hampers treatment responses.

What is the main cause of treatment failure after endocrine therapy?

Resistance to endocrine therapy develops, leading to disease progression such as castration-resistant prostate cancer and reduced long-term survival. Mechanisms include receptor alterations, reliance on non-hormone pathways, dysregulated hormone signaling, and an increasingly immunosuppressive TME.

How does reprogramming tumor-associated macrophages improve anti-tumor immunity?

Reprogramming TAMs within solid tumors aims to restore their natural capacity to fight cancer. This approach can also enhance the antitumoral effects of endocrine therapy, including demonstrated synergy with androgen deprivation therapy in preclinical models.

Sep 23, 2026

Uploaded by Stanley