Immunotherapy for cancer aims to eliminate or control tumors by activating or enhancing the patient's own immune system, providing passive or active immunity against malignant tumors. Currently, commonly used cancer immunotherapies in clinical practice include immune checkpoint inhibitors (ICIs), adoptive cell transfer, cancer vaccines, cytokine therapy, oncolytic virus therapy, bispecific antibodies, etc. (Klein et al., 2024, Rui et al., 2023, Zhang and Zhang, 2020). ICIs such as PD-1/PD-L1 inhibitors and CTLA-4 inhibitors can target the dysfunctional immune system and restore the anti-tumor activity of T cells, achieving significant therapeutic effects in various cancers such as melanoma (Carlino et al., 2021), non-small cell lung cancer (Reck et al., 2022). Adoptive cell transfer utilizes autologous immune cells. By genetically engineering T cells to specifically recognize and kill cancer cells, it has shown good therapeutic effects in neuroblastoma, leukemia, and lymphoma (Restifo et al., 2012). In addition, cancer vaccines such as Sipuleucel-T activate the immune system by introducing tumor-specific antigens (Li et al., 2023), reducing the risk of death in men with castration-resistant prostate cancer (Kantoff et al., 2010). Cytokine therapy such as Interleukin-2 (IL-2) can enhance the function of immune cells and is used to treat metastatic renal cell carcinoma and metastatic melanoma (Rosenberg, 2014). Oncolytic viruses such as T-VEC selectively infect tumor cells and activate the immune response, which are used for the treatment of melanoma (Poh, 2016). Bispecific antibodies designed for T cells can bind simultaneously to antigens on tumor cells and the CD3 subunit on T cells, recruiting T cells into the tumor microenvironment (TME) to enhance the anti-tumor effect (van de Donk and Zweegman, 2023). The above methods all provide diverse strategies for cancer treatment.

Immunotherapy has made remarkable progress in breast cancer treatment in recent years. ICIs such as Pembrolizumab have been approved for the treatment of PD-L1 positive advanced or metastatic triple-negative breast cancer (TNBC), and the combination with chemotherapy can significantly prolong the progression-free survival and overall survival (OS) of patients (Cortes et al., 2020, Cortes et al., 2022). In addition, Chimeric Antigen Receptor T-cell (CAR-T) therapy and personalized cancer vaccines also show potential application prospects in clinical trials (Huang et al., 2022, Suchiita and Sonkar, 2025, Yang et al., 2022), especially vaccines for HER2-positive breast cancer and specific neoantigens (McCarthy et al., 2021). However, immunotherapy for breast cancer still faces many challenges, including low immunogenicity of some subtypes of tumors (Zhao and Huang, 2020), the immunosuppressive state of the TME (Naji et al., 2024), the high heterogeneity of breast cancer (Zhao and Rosen, 2022), and treatment resistance (Nolan et al., 2023). Therefore, exploring the reasons for the changes in the immune status in the TME, developing targeted drugs to reshape the immune microenvironment, using omics technologies to identify key driver genes and resistance mechanisms in the progression of breast cancer, and exploring the synergistic effects of immunotherapy and other therapies will become the research focus.

As a crucial component of immunotherapy, cytokine therapy directly acts on various stages of immune cell activation, proliferation, and effector functions (Hough et al., 2023, Manzano and Caffarel, 2025, Propper and Balkwill, 2022, Zarezadeh Mehrabadi et al., 2024). It possesses multiple unique advantages, such as simultaneously activating different types of immune cells, inducing characteristics of innate immune responses, and promoting the formation of immunological memory, thereby exerting distinct benefits in tumor treatment (Cao and Kagan, 2023, Terrén et al., 2022). The cytokines IL-2 and IFN-α have been approved for clinical use (El Bitar and Arcasoy, 2024, Manzano and Caffarel, 2025). However, the significant systemic toxicity and limited efficacy (Aranez and Ambrus, 2020, Vial and Descotes, 1995) associated with these cytokines have driven researchers to explore safer and more targeted alternatives. In this context, granulocyte-macrophage colony-stimulating factor (GM-CSF) has emerged as a multifunctional cytokine and been widely applied in cancer treatment. As a hematopoietic growth factor, GM-CSF can alleviate the bone marrow suppression in cancer patients caused by chemotherapy or radiotherapy and promote the recovery of neutrophils and monocytes (Vadhan-Raj et al., 1988). With the in-depth research, the immunomodulatory function of GM-CSF has been gradually discovered, especially its effects on activating dendritic cells (DCs) (Caux et al., 1992), macrophages (Becher et al., 2016), and T cells (Dranoff, 2002), which suggests that GM-CSF can serve as an important target for immunotherapy. The combination of GM-CSF with ICIs PD-1 inhibitor and CTLA-4 inhibitor shows a synergistic anti-tumor effect (Curran et al., 2010). In addition, GM-CSF has also been used to support CAR-T therapy and maintain the effector function of T cells. Interestingly, GM-CSF exhibits a dual role, acting as either an immune stimulant or an immune suppressant in various types of tumors, such as melanoma, lung cancer, colorectal cancer, pancreatic cancer, renal cell carcinoma, bladder cancer, prostate cancer, hematological malignancies, glioblastoma. (Table 1). This dual role presents certain challenges for the clinical application of GM-CSF in tumor therapy. In the treatment of breast cancer, GM-CSF can be used in combination with HER2 vaccine or anti-HER2 antibody to activate the T cell-mediated anti-tumor immune response and enhance the antibody-dependent cell-mediated cytotoxicity effect, exerting a synergistic therapeutic effect (Zhou, 2023). GM-CSF also has a dual role in the TME of breast cancer. It may either activate the anti-tumor immune response or promote the activation of immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), M2-type tumor-associated macrophages (TAMs) (Hamilton, 2008, Helft et al., 2015, Li et al., 2023). In addition, GM-CSF can directly act on breast cancer cells, promoting the proliferation and metastasis of tumor cells. Therefore, the application strategy of GM-CSF in breast cancer still needs further optimization.

This review summarizes the dynamic dual-regulatory network of GM-CSF in the breast cancer immune microenvironment, overcoming the limitations of traditional single-mechanism research paradigms. By integrating multidimensional evidence, we systematically elucidate the spatiotemporally specific regulatory mechanisms of GM-CSF within the TME, while comprehensively evaluating its clinical applications from a translational perspective. The present work provides in-depth discussion on both the translational potential and critical challenges of GM-CSF from basic research to clinical practice, establishing not only a novel theoretical framework for understanding the complex biological functions of GM-CSF, but also offering valuable references for optimizing precision immunotherapy strategies in breast cancer.