This review explores how the immunosuppressive TME in breast cancer blocks effective immune activation and impairs immunotherapy ¹. Dominant immune-suppressive cells- Tregs, MDSCs, and TAMs—release cytokines such as IL-35, IL-10, and TGF-β, which contribute to T cell exclusion and dysfunction ². We discuss how this immune barrier is particularly pronounced in hormone receptor-positive and triple-negative subtypes ¹. Emerging interventions—including checkpoint blockade, mRNA vaccines, and oncolytic viruses—aim to remodel the TME and support cold-to-hot tumor transformation for improved immunotherapeutic response ³.

The Need for Reprogramming the TME

The breast cancer TME typically lacks sufficient immune infiltration and is dominated by suppressive cells that block antitumor immunity. Tregs, MDSCs, and TAMs disrupt immune activation, while poor antigen presentation and high levels of checkpoint receptors like PD-1, TIGIT, and LAG-3 further restrict T cell function ^4,5. Reprogramming this environment is essential to drive a shift toward a “hot” TME. Doing so enhances cytotoxic T cell access and activity, enabling immunotherapies to overcome resistance and achieve better clinical outcomes ^6-8.

Advancements and Scientific Significance

Recent advancements in breast cancer immunotherapy have focused on overcoming the cold TME ⁹. ICIs targeting PD-1, LAG-3, and TIGIT have shown promise, particularly when combined with therapies that induce immunogenic cell death or enhance immune cell activation, such as CAR T-cell therapies. mRNA vaccines have emerged as a potential tool to enhance T cell responses by increasing antigen presentation ¹⁰. These strategies, when used together, aim to convert the immunologically inert TME into a more active one, improving the overall efficacy of immunotherapies ¹¹.

Inspiration for the Study

This review is inspired by recent advances in cancer immunotherapy and the evolving understanding of the TME, particularly the role of the microbiome ¹. Emerging evidence indicates that both gut and tumor-associated microbiota significantly shape systemic and local immune responses, influencing the efficacy of immunotherapies across various cancer types, including breast cancer ^12-14. Another key development is the identification of neo-antigens—tumor-specific peptides generated from somatic mutations—which provide promising targets for personalized immunotherapy. mRNA-based vaccines targeting clonal neo-epitopes, such as those derived from PIK3CA, TP53, or ESR1 mutations, have demonstrated the capacity to enhance cytotoxic CD8+ T cell responses and improve tumor recognition ^15-18.

Importantly, these approaches are particularly relevant given the molecular heterogeneity of breast cancer. In HR⁺/HER2^– tumors, often driven by ESR1 mutations and enriched in luminal gene expression profiles, the TME is characterized by low MHC-I expression and minimal CD8⁺ T cell infiltration. Heating strategies in this context may include STING agonists or IL-2 variants to promote dendritic cell activation and T cell recruitment. In HER2+ subtypes, frequently associated with ERBB2 amplification, resistance to trastuzumab has been linked to immune escape mechanisms such as PD-L1 upregulation; thus, mRNA vaccines encoding HER2-derived neoepitopes or co-administration with GM-CSF may potentiate immune activation. Triple-negative breast cancer (TNBC), often harboring TP53 mutations and basal-like signatures, displays elevated tumor-infiltrating lymphocytes (TILs) and PD-L1 expression, making it amenable to immune checkpoint blockade. Nonetheless, immune efficacy may be further enhanced through mRNA vaccines targeting clonal neoantigens or shared tumor-associated antigens (TAAs) such as NY-ESO-1 or MAGE-A, especially when coupled with microbiome modulation using Bifidobacterium or Faecalibacterium ^19,20.

The concept of “heating” the TME—converting immune-cold or excluded tumors into inflamed, T cell–rich environments—enables a paradigm shift from passive to active immunotherapy. By integrating neoantigen prediction, microbiota engineering, and mRNA vaccine platforms, even immunologically inert subtypes may be sensitized to advanced immunotherapeutic modalities, including mesothelin-targeted CAR-T cells, cancer stem-like cell-directed therapies, CTLA-4 blockade, and next-generation neoantigen-based mRNA vaccines across the molecular spectrum of breast cancer ^21-23.

Future Directions

Reprogramming the TME from cold to hot involves boosting immune cell infiltration and overcoming the immunosuppressive barriers that limit the effectiveness of therapies like ICIs. In cold tumors, such as TNBC, the TME is typically hostile to immune cells, with immune-excluded regions dominated by Tregs, MDSCs, and TAMs. These suppressive cells hinder immune activation and allow the tumor to evade immune surveillance ⁷.

Targeting these immune-suppressive cells directly is essential. For example, therapies aimed at depleting Tregs or blocking MDSC activity can make the TME more permissive to immune cell infiltration. Additionally, addressing stromal factors like hypoxia and lactate accumulation, which promote immune suppression, can further help "Heat-Up" the TME by improving the conditions for immune cells to thrive ¹¹.

In TNBC, which often lacks effective immune responses, reprogramming the TME is crucial. This can be achieved by targeting the suppressive elements within the TME, making the tumor more vulnerable to immune activation. Strategies like combining TME modulation with mRNA vaccines or oncolytic virus therapy could further enhance immune responses, especially in TNBC, which otherwise resists conventional treatments ^24,25.

Immunosculpting, the process by which tumors establish niches that shape immune responses, plays a significant role in cold tumor resistance. TNBC and other subtypes exploit these niches to prevent immune cells from infiltrating or recognizing the tumor. Novel approaches are being explored to target these immune-excluded regions with immunostimulatory agents, thereby increasing immune activation within the tumor .

In luminal breast cancer, chemotherapy-induced cell death (ICD) has shown promise in transforming cold tumors to hot ones by inducing immune responses. However, resistance remains a challenge, particularly in HER2-positive cancers, where tumors can shed HER2 or activate immune checkpoints like PD-L1, which blocks the immune response. To combat this, combination therapies—such as pairing ICIs with chemotherapy or targeted therapies—are being tested to overcome these mechanisms of resistance ^26-28.

The future of breast cancer treatment lies in refining strategies to modulate the TME effectively. Key directions include developing therapies targeting alternative immune checkpoints, such as LAG-3 and TIGIT, which could enhance immune responses. Additionally, improving patient selection through better biomarkers will ensure that therapies are directed to those who will benefit the most ^29,30. By addressing the complexity of the TME and immune resistance mechanisms, these approaches can potentially transform the landscape of breast cancer immunotherapy.

Summary

This paper emphasizes the importance of reprogramming the TME to overcome immune exclusion and resistance in breast cancer. Combining immune checkpoint inhibitors, CAR T-cell therapies, and mRNA vaccines, strategies are emerging that can convert cold tumors into hot, immunologically responsive ones. These therapies offer hope for improving patient outcomes, especially for difficult-to-treat subtypes like HR+, TNBC, and HER2+ breast cancer.

About Authors

Saber Imani is an independent Assistant Professor at Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China. He leads a research lab advancing mRNA-based cancer vaccines and translational oncology. His work focuses on unraveling the molecular mechanisms underlying cancer and viral diseases, with particular emphasis on ICIs and the role of immunotherapy in cancer treatment. Through his leadership, his lab critically contributes to developing innovative cancer therapies, aiming to reprogram the TME for enhanced anti-tumor responses. By targeting key immunological pathways and advancing strategies like ICI-based therapy and mRNA vaccination, his research holds the potential to address global health challenges and improve cancer treatment outcomes.

Ghazaal Roozitalab is a surgical assistant who graduated with a degree in anesthesia nursing from Fasa University of Medical Sciences. Passionate about integrating clinical practice with cutting-edge research, her interests span nano‑drug delivery systems, cancer immunotherapy, and biotechnology. Driven by curiosity, Ghazaal adopts a question-oriented approach to pinpoint gaps in scientific knowledge and inspire innovative solutions. In close collaboration with Dr. Parham Jabbarzadeh Kaboli, she contributes to multiple interdisciplinary projects to advance targeted cancer therapies.

Mazaher Maghsoudloo holds a PhD in Bioinformatics from Tehran University, where he graduated in 2020. With a background in Computer Science, he combines computational expertise with a deep understanding of biological systems. Since 2023, he has been serving as a Research Associate at Southwest Medical University, working in the Key Laboratory of Epigenetics and Oncology within the Research Center for Preclinical Medicine. His research focuses on cancer biology, particularly on biomarker detection and the reconstruction of disease networks, with a special emphasis on cancer-related applications. He works closely with Dr. Saber Imani, and together they lead collaborative efforts in advancing mRNA-based cancer vaccines, translational oncology, and research on various cancers, emphasizing ICIs and immunotherapy. Through this collaboration, they aim to reprogram the TME and develop innovative therapeutic strategies to enhance anti-tumor responses and improve cancer treatment outcomes.

Parham Jabbarzadeh Kaboli is a dedicated cancer researcher based in the United States. He earned his Ph.D. in Pharmacology from Universiti Putra Malaysia in 2018 and maintains an h-index of 25 with over 1,900 citations. His research primarily centers on developing targeted therapies and uncovering resistance mechanisms in breast cancer. Dr. Kaboli has published impactful studies, mentored emerging scientists, and worked under distinguished mentors in Malaysia, China, Taiwan, and the U.S. During his postdoctoral fellowship at China Medical University in Taiwan, he conducted pioneering research on the c-MET receptor tyrosine kinase. Aiming to overcome drug resistance in solid tumors, Dr. Kaboli plans to establish a research program that integrates immunotherapy with clinical applications. He remains committed to training the next generation of scientists and excels in cross-cultural collaboration.

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