Immunotherapy in breast cancer: current landscape and emerging trends

Abstract

Breast cancer remains one of the most prevalent malignancies worldwide, underscoring an urgent need for innovative therapeutic strategies. Immunotherapy has emerged as a transformative frontier in this context. In triple-negative breast cancer (TNBC), the combination of immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors (ICIs) with chemotherapy has proven efficacious in both early and advanced clinical trials. These encouraging results have led to the approval of ICIs for TNBC, opening up new therapeutic avenues for challenging-to-treat patient populations. Furthermore, a multitude of ongoing trials are actively investigating the efficacy of immunotherapy-based combinations, including ICIs in conjunction with chemotherapy, targeted therapy and radiation therapy, as well as other novel strategies such as bispecific antibodies, CAR-T cells and cancer vaccines across all breast cancer subtypes, including HR-positive/HER2-negative and HER2-positive disease. This review provides a comprehensive overview of current immunotherapeutic approaches in breast cancer, highlighting pivotal findings from recent clinical trials and the potential impact of these advancements on patient outcomes.

Keywords: Breast cancer; Clinical trials; Combination therapy; Immune-checkpoint inhibitors; Immunotherapy.

Fig. 1

Historic landmark clinical trials of ICI combined with chemotherapy for TNBC. Blue boxes represent clinical trials in advanced settings, green boxes represent clinical trials in neoadjuvant settings, and yellow boxes represent clinical trials in adjuvant settings. Abbreviations: CT chemotherapy, FDA Food and Drug Administration, NMPA National Medical Products Administration, TNBC triple-negative breast cancer

Fig. 2

Factors related to immunotherapy response and multi-omics integration to explore immunotherapy benefit population in breast cancer. Shao et al. performed an integrated multi-omics profiling of the three traditional breast cancer subtypes TNBCs, HER2 + and HR + /HER2–, and reclassified them into four subtypes, of which immunomodulatory and immunogenic subtypes, featuring enriched immune cells and immune-activated microenvironment, potentially benefit from ICI therapy [–133]. Intrinsic and extrinsic features of cancer cells, including host immunity, can influence the response to ICIs targeting the PD-1/PD-L1 axis. Comprehensive evaluation of such factors may be pivotal to select patients that are more likely to respond to ICI [134]. Abbreviations: Ab antibody, ACTs adoptive cell therapies, Amp amplification, B2M β2-microglobulin, BLIS basal-like immune-suppressed, BM basal/mesenchymal-like, CPS combined positive score, CTC circulating tumor cells, ctDNA circulating tumor DNA, DCs dendritic cells, dMMR mismatch repair deficiency, CLA classical, ICs immune cells, ECM extracellular matrix, EMT epithelial-mesenchymal transition, ER estrogen receptor, GEP gene expression profile, GZMB Granzyme B, HER2 human epidermal growth factor receptor 2, HR hormone receptor, HLA human leukocyte antigen, ICI immune checkpoint inhibitor, IHC immunohistochemistry, IFN interferon, IDO1 indoleamine2,3-dioxygenase1, LAG-3 lymphocyte-activation gene 3, LAR luminal androgen receptor, LDH lactate dehydrogenase, LUM luminal-like, MES mesenchymal-like, MHC major histocompatibility complex, Mut mutation, MSI-H high microsatellite instability, Mφ macrophage, PDO patient-derived organoids, PD-L1 programmed death-ligand 1, PDX patient-derived xenografts, PFN perforin, sCD163 soluble variant of CD163, SCNAs somatic copy number alteration, RTK receptor tyrosine kinase, TCR T cell receptor, TIL tumor-infiltrating lymphocyte, TLS tertiary lymphoid structures, TMB tumor mutational burden, TNBC triple-negative breast cancer, TNF tumour necrosis factor, TRM tissue-resident memory

Fig. 3

Combination partners for ICI and emerging immunotherapy strategies. Abbreviations: Ab antibody, ADC antibody–drug conjugate, ADCC antibody-dependent cell-mediated cytotoxicity, ADM doxorubicin, AKTi AKT inhibitor, APC antigen-presenting cell, BC breast cancer, BsAb bispecific antibody, CAP Capecitabine, CAR T cell chimeric antigen receptor T cell, CDK4/6i cyclin-dependent kinase 4/6 inhibitor, CTLA-4 cytotoxic T-lymphocyte–associated protein 4, CTX cyclophosphamide, DDP cisplatin, DTX docetaxel, EPI epirubicin, 5-Fu 5-Fluorouracil, GEM gemcitabine, HER2 human epidermal growth factor receptor 2, ICI immune checkpoint inhibitors, LAG-3 lymphocyte-activation gene 3, MHC major histocompatibility complex, NVB vinorelbine, PARP poly (ADP-ribose) polymerase, MEKi mitogen-activated extracellular signal-regulated kinase inhibitor, TKI tyrosine kinase inhibitors, PD-L1 programmed death-ligand 1, PD-1 programmed cell death protein, PTX paclitaxel, TIM-3 T cell immunoglobulin and mucin domain-3 protein, TIGIT T cell immunoglobulin and ITIM domain, TILs tumor infltrating lymphocytes, TCR T cell receptor

Fig. 4

The application and prospects for AI in breast cancer immunotherapy. Abbreviations: AI artificial intelligence, AI-CDSS artificial intelligence-powered clinical decision support systems, AIDD artificial intelligence-driven drug design, BC breast cancer, irAEs immune-related adverse events, MSI microsatellite instability, PD-L1 programmed death-ligand 1, TILs tumor infiltrating lymphocytes, TMB tumor mutational burden