Peptide-mediated immunomodulation of tumor microenvironment in triple-negative breast cancer: A comprehensive review

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. The absence of molecular targets in TNBC limits treatment options and contributes to increased rates of recurrence, metastasis, and resistance to conventional therapies. TNBC, however, is rich in tumor-infiltrating lymphocytes; hence, elevated programmed death-ligand 1 expression makes these tumors amenable to immunotherapy. A variety of antibodies and immunomodulatory drugs are being explored for TNBC treatment, this review specifically focuses on design of immunomodulatory peptides for TNBC treatment. This review comprehensively discusses the peptide-based approaches for immunomodulating tumor microenvironment (TME) of TNBC and to enhance antitumor immune response. The peptide-mediated modulation of innate immune cells including tumor-associated macrophages, neutrophils, dendritic cells, and natural killer cells, as well as T cells of the adaptive immune system is explored in detail. The applications of peptides as immune checkpoint inhibitors and highlights of emerging strategies that employ peptides to induce immunogenic cell death to stimulate antitumor immunity are discussed. Immunogenic cell death inducing peptides promote the release of immunogenic signals such as damage-associated molecular patterns from dying cancer cells, which further activate dendritic cells, T cells, and neutrophils, thereby reshaping the TME to support robust antitumor immunity. These strategies underscore the transformative potential of peptide therapeutics to harness the immune system and reshape TME, offering a promising avenue for more effective and durable TNBC treatment. SIGNIFICANCE STATEMENT: With growing interest in peptides as tumor microenvironment modulator, this review provides an in-depth analysis of interactions and crosstalk between immune and tumor cells and explores therapeutic potential of peptides in modulating immune cell signaling pathways, with ultimate impact as anticancer agents for triple-negative breast cancer.