Comprehensive review of drug-mediated ICD inhibition of breast cancer: mechanism, status, and prospects

Abstract

The escalating incidence of breast cancer (BC) in women underscores its grave health threat. Current molecular insights into BC's post-adjuvant therapy cure remain elusive, necessitating active treatment explorations. Immunotherapy, notably chemotherapy-induced immunogenic cell death (ICD), has emerged as a promising BC therapy. ICD harnesses chemotherapeutics to activate anti-tumor immunity via DAMPs, fostering long-term T-cell memory and primary BC cure. Besides chemotherapy drugs, Nanodrugs, traditional Chinese medicine (TCM) and ICIs also induce ICD, boosting immune response. ICIs, like PD-1/PD-L1 inhibitors, revolutionize cancer treatment but face limited success in cold tumors. Thus, ICD induction combined with ICIs is studied extensively for BC immunotherapy. This article reviews the mechanism of ICD related drugs in BC and provides reference for the research and development of BC treatment, in order to explore more effective clinical treatment of BC, we hope to explore more ICD inducers and make ICIs more effective vaccines.

Keywords: Breast cancer; ICD; ICIs; Mechanism; TME; immunotherapy.

Fig. 1

The mechanism diagram of ICD inducer inhibiting breast tumor cells. After receiving ICD inducer, breast tumor cells gradually die and release DAMPs (ATP, CRT, and HMGB1) to bind to specific receptors to promote the maturation of DCs and the production of IL-1. DCs in turn produce γ/δ T cells and CTLs, both of which mediate direct antitumor activity by secreting IFN-γ, perforin, and granzyme

Fig. 2

The mechanism diagram of ICD inducer inhibiting breast tumor cells through the release of CRT. In ER, CRT can regulate Ca²⁺ homeostasis. In the early stage of immunogenic death, after treatment, ER stress kinase PERK was activated and further eIF2a phosphorylation occurred, then caspase-8 mediates partial activation of Bax and Bak, induces CRT exposure to the cell surface, and CRT sends “eat me” signal to antigen-presenting cells, which promotes DC to trigger tumor antigen presentation and tumor-specific CTL response, so that CTL is activated and differentiated into CTL with tumor killing activity, which further specifically kills breast tumor cells

Fig. 3

The mechanism diagram of ICD inducer inhibiting breast tumor cells through the release of ATP. After treatment with ICD inducer, breast tumor cells were in a dying state and released a large amount of ATP, ATP sends out a “find me” signal, and the receptor on monocytes immediately induces the recruitment and apoptosis signal to drive the secretion of IL-1β. IL-1β antigen induces DC activation and tumor antigens are presented to CD4⁺T and CD8⁺T lymphocytes, which directly act on breast tumor cells and promote anti-tumor immune response

Fig. 4

The mechanism diagram of ICD inducer inhibiting breast tumor cells through the release of HMGB1. HMGB1 in the nucleus regulates the structure and function of chromosomes, while HMGB1 in the cytoplasm maintains autophagy. Extracellular, ICD inducer makes breast tumor cells in a dying state, promotes the release of HMGB1, and then activates downstream NF- κB and MAPK signaling pathways through a specific receptor TLR4, which orchestrates the creation of inflammatory factors IL-17 and IL-1β receptor, so as to exert the effect of anti-breast tumor immunotherapy