A Systematic Review of Immune Cell Roles in Breast Cancer Immunotherapy

Abstract

Background: Breast cancer (BC) is the most prevalent malignancy among women and is associated with high mortality and significant clinical challenges. Although conventional treatments such as surgery, chemotherapy, and radiotherapy have significantly improved patient survival, their efficacy remains limited by severe side effects and treatment resistance. In recent years, advances in immunotherapy have underscored the pivotal role of immune cells in treating BC.

Recent findings: This systematic review summarizes the current knowledge on the roles of immune cells within the BC tumor microenvironment (TME), including their phenotypes, functions, and implications for immunotherapy. Following PRISMA guidelines, 71 studies published between 2010 and 2024 were analyzed. The results indicate that immune cell populations-such as tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), natural killer (NK) cells, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs)-are integral to tumor progression and therapeutic response. However, their functional heterogeneity and plasticity remain key obstacles to the development of effective and personalized immunotherapeutic strategies.

Conclusion: Further research is needed to clarify the mechanisms governing immune cell behavior within the BC TME and to advance precision immunotherapy. Such insights will lay the foundation for individualized treatment approaches, ultimately improving patient outcomes and quality of life (QoL).

Keywords: breast cancer; immune cells; immunotherapy; tumor microenvironment; vaccines.

FIGURE 1

Graphical abstract illustrating the role and future prospects of immune cells in breast cancer therapy. This schematic summarizes the complex interplay among breast cancer (BC) cells (red), tumor‐associated antigens (including HER2, mucin 1, and α‐lactalbumin), and various immune cells such as dendritic cells (DCs), macrophages, T cells, B cells, and natural killer (NK) cells. The therapeutic strategies depicted include antigen‐targeted vaccines (HER‐2 vaccine, peptide vaccine, viral vector vaccine, α‐lactalbumin vaccine, and nano vaccines), cellular immunotherapies (CAR‐T cells, CAR‐macrophages, NK cell therapy, and adoptive T cell therapy), immune checkpoint modulation (CTLA‐4 antagonists and STING agonists), metabolic regulators, and innovative bispecific antibodies. Collectively, these approaches enhance antitumor immunity by activating effector immune cells, reversing tumor‐induced immunosuppression, and remodeling the tumor microenvironment (TME), thereby underscoring the potential for personalized and combination therapies in BC.

FIGURE 2

Literature selection flowchart based on the PRISMA 2020 Checklist. A total of 2601 records were initially identified through database searches, with the same number remaining after duplicate removal. Following a preliminary screening of titles and abstracts, 2082 records were excluded, leaving 519 records for full‐text review. After detailed evaluation, 426 records that did not meet the inclusion criteria were excluded, resulting in the final inclusion of 71 studies for the review. Detailed selection criteria and processes are provided in Supporting Information.

FIGURE 3

Interactions and regulatory mechanisms of immune cells within the breast cancer tumor microenvironment (TME). This schematic illustrates the diverse immune cell populations and their complex interactions within the BC TME. Tumor‐associated macrophages (M1/M2 TAMs) influence tumor progression by secreting cytokines (e.g., SPP1, PD‐L1), promoting tumor growth and immune evasion. Cytotoxic T lymphocytes (CTLs) and NK cells mediate direct tumor cell killing via granzyme B, perforin, FASL/TRAIL, and cytokines (IFNγ, TNFα). Dendritic cells (DCs), including conventional DCs (cDCs) and plasmacytoid DCs (pDCs), coordinate adaptive immunity through antigen presentation and regulation of angiogenesis. B and plasma cells (PCs) contribute to antitumor responses via antibody‐dependent cell‐mediated cytotoxicity (ADCC). Neutrophils exhibit dual phenotypes (N1 and N2), regulated by cytokines (IFN‐β, TGF‐β), which affect tumor progression and immunosuppression. In addition, monocytes differentiate into polarized macrophages, modulating local inflammation, while chemokines (CCL19, CCL21, CXCL12, CXCL13) recruit various immune cells to shape the immune milieu further. Intrinsic tumor signaling pathways (AKT, STAT3) promote tumor progression and immune evasion by inducing PD‐L1 expression. Overall, these interactions define the immune microenvironment in BC and represent promising therapeutic targets.

FIGURE 4

Schematic diagram of emerging immune cell subpopulations and their interactions in the breast cancer immune microenvironment. This figure highlights the principal immune cell subsets within the BC microenvironment and their key secreted factors, including Bregs, Tregs, MDSCs, Th17 cells, effector T cells (Teff), innate lymphoid cells (ILC1), and CCL18⁺ M2 macrophages. Solid and dashed arrows denote direct or indirect regulatory relationships among these cells; annotations indicate secreted cytokines (e.g., IL‐10, IL‐35, TGF‐β, IL‐17, IFNγ, IL15, CCL18) and key signaling pathways (e.g., Hedgehog/Hd signal). The interplay among these immune cells establishes an immunosuppressive microenvironment that promotes tumor growth and metastasis while offering potential targets for tailored immunotherapy.

FIGURE 5

Schematic of breast cancer immunotherapy strategies and their mechanisms of interaction. This figure depicts the interplay between BC cells (red) and common tumor‐associated antigens (HER‐2, mucin 1, αlactalbumin) with various emerging immunotherapeutic strategies. Dendritic cells (DCs) act as a bridge by presenting antigens and activating CD4⁺ and CD8⁺ T cells to initiate and enhance the adaptive immune response. Additionally, several vaccine strategies (including HER2, peptide, viral vector, α‐lactalbumin, and nano vaccines) directly target tumor antigens to exert antitumor effects, while combination with immune checkpoint inhibitors further amplifies the immune response. Other emerging immunomodulatory approaches—such as STING agonists, CAR‐macrophages, NK cell therapy, metabolic regulators, CTLA‐4 antagonists, and CAR‐T cell therapy—enhance therapeutic outcomes by boosting innate immunity, improving the tumor microenvironment, or directly targeting tumor cells. Integrating these diverse immunotherapeutic strategies collectively provides robust support and a theoretical basis for improving clinical outcomes in BC.