Breast cancer remains a leading cause of cancer-related death among women worldwide. Despite advances in screening, diagnosis, and traditional therapies like surgery, chemotherapy, and radiation, a significant number of patients experience disease recurrence or metastasis. With the advent of immunotherapy, the landscape of breast cancer treatment is evolving. The clinical application of immunotherapy, particularly the blockade of immune checkpoints such as Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1 (PD-L1), has marked a new frontier in the management of various malignancies. Triple-negative breast cancer (TNBC), characterized by higher tumor mutational load and immune cell infiltration, has been the primary focus in this respect. However, developing novel therapeutic strategies targeting additional immune-related molecules is essential to broaden the scope of breast cancer patients who can benefit from immunotherapy. This news article delves into emerging targets for breast cancer immunotherapy beyond PD-1/PD-L1 inhibition.

Emerging Immunotherapeutic Targets in Breast Cancer

Tumor evasion from the immune system is a complex and multifaceted process involving various co-stimulatory or co-inhibitory molecules that regulate the tumor-host interaction. The biological role, prognostic, and predictive implications concerning breast cancer, and the early clinical efforts to exploit these novel immune-related therapeutic targets are pressing concerns. Co-stimulatory and co-inhibitory molecules such as Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4), LAG-3, TIM-3, TIGIT, CD70, and IDO are now recognized for their significant roles in tumor immunosurveillance and are promising targets for breast cancer therapy.

LAG-3 and TIM-3: Key Checkpoint Inhibitors

Lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin mucin-3 (TIM-3) are two checkpoints with growing interest in cancer therapy. LAG-3, expressed on the surface of activated T cells, regulatory T cells (Tregs), and natural killer (NK) cells, binds to major histocompatibility complex (MHC) class II molecules, playing a critical role in controlling T cell response. Blocking the LAG-3 pathway has been shown to improve anti-tumor immunity, making it a viable target for cancer immunotherapy. Similarly, TIM-3, expressed on T cells and innate immune cells, serves as a negative regulator of immune responses. Inhibition of TIM-3 has the potential to restore exhausted T cell function and enhance anti-tumor activity.

TIGIT and CD70/CD27 Axis: Immune Modulators with Therapeutic Potential

TIGIT (T cell immunoreceptor with Ig and ITIM domains) is an inhibitory receptor that can suppress T and NK cell activity when engaged with its ligands CD155 and CD112. Recent studies have shown that dual blockade of TIGIT and PD-1 could synergistically enhance immune responses against cancer. Another axis of interest is the interaction between CD70 on the surface of cancer cells and CD27 on T cells. This interaction can shape the immune response, and targeting this pathway could promote T cell activation and proliferation.

IDO: Metabolic Enzyme as an Immune Regulator

Indoleamine 2,3-dioxygenase (IDO) is an enzyme that catalyzes the conversion of tryptophan to kynurenine, leading to an immunosuppressive tumor microenvironment. IDO expression is associated with Treg infiltration and suppression of anti-tumor T cell responses. IDO inhibitors, combined with other immunotherapies like PD-1/PD-L1 blockade, have shown promising results in early clinical trials.

Clinical Implications and Future Directions

Immunotherapy has revolutionized the treatment of various cancers, and breast cancer is no exception. The discovery of new immune-related targets, such as LAG-3, TIM-3, TIGIT, CD70/CD27, and IDO, presents opportunities to improve patient outcomes, especially for those not responding to current treatment regimens. Ongoing research and clinical trials are essential to translate these promising targets into effective therapies for breast cancer patients.


The future of breast cancer immunotherapy lies in targeting a broader range of immune-related molecules, which may significantly enhance antitumor responses. Novel agents aimed at LAG-3, TIM-3, TIGIT, CD70/CD27, and IDO are already being evaluated in clinical trials, with the potential to complement or even surpass the efficacy of current PD-1/PD-L1 inhibitors. The successful translation of these emerging targets into routine clinical practice may herald a new era in breast cancer treatment where more patients can achieve lasting remissions.


1. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013. [PMC Free Article] [PubMed] 2. [(accessed on 24 March 2019)]; Available online:
3. Denkert C., et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19:40–50. doi: 10.1016/S1470-2045(17)30904-X. [PMC Free Article] [PubMed] 4. Foukakis T., et al. Immune gene expression and response to chemotherapy in advanced breast cancer. Br. J. Cancer. 2018;118:480–488. doi: 10.1038/bjc.2017.446. [PMC Free Article] [PubMed] 5. Ogiya R., et al. Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer patients. Cancer Sci. 2016;107:1730–1735. doi: 10.1111/cas.13101. [PMC Free Article] [PubMed] 6. Kassardjian A., et al. Expression of immune checkpoint regulators, cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death-ligand 1 (PD-L1), in female breast carcinomas. PLoS ONE. 2018;13:e0195958. doi: 10.1371/journal.pone.0195958. [PMC Free Article] [PubMed] 7. Schmid P., et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N. Engl. J. Med. 2018;379:2108–2121. doi: 10.1056/NEJMoa1809615. [PubMed] 8. Adams S., et al. Current Landscape of Immunotherapy in Breast Cancer: A Review. JAMA Oncol. 2019 doi: 10.1001/jamaoncol.2018.7147. [PMC Free Article] [PubMed]


1. Breast Cancer Immunotherapy
2. Emerging Immunotherapeutic Targets
3. IDO inhibitors
4. Triple-negative breast cancer
5. Clinical trials
6. Novel immune checkpoints
7.Immune regulation