Faith Haugen

Background: Triple negative breast cancer (TNBC) is an cancer subtype defined by the absence of estrogen, progesterone, and human epidermal growth factor 2 (HER2) receptors.⁶ The lack of these receptors leaves proliferative signaling pathways unchecked and significantly limits the availability of targeted therapies.⁶ Current treatment approaches rely predominantly on cytotoxic chemotherapy and immune checkpoint inhibitors (ICI). However, the objective response rate of ICI combined with chemotherapy is estimated at 20% in the metastatic setting, highlighting the heterogeneous and treatment-resistant nature of this disease.⁶ TNBC is further associated with high rates of late-stage diagnosis, early recurrence, and significant health disparities, including higher prevalence among younger women and those with BRCA1/2 germline mutations.⁷ Growing interest in radioimmunotherapy as a combinatory treatment strategy further dissects the relationship between tumor-resident myeloid cells and their activation by radioimmunotherapy to supplement anti-tumor immune responses.

Objective: In this narrative review, I explored how myeloid-T cell crosstalk within the tumor microenvironment mediates response to radioimmunotherapy in TNBC and examined emerging therapeutic strategies which enhance myeloid cell activity.

Search Methods: A literature search within PubMed was conducted from 2019 to 2026 using the following MeSH keywords: “Breast neoplasm,” “Metastatic,” “Innate immune system,” “Antibody,” “Radioimmunotherapy,” and “Tumor microenvironment.”

Results: Upon pertinent literature review, influence of phenotype and spatial organization of myeloid cells within the TME are critical determinants of radioimmunotherapy response in TNBC. Using single-cell and spatial profiling, three distinct immune states were identified following combination pembrolizumab and focal radiotherapy exposure.¹ These groupings were early responders (R1) with pre-existing high immune cell density, late responders (R2) with low baseline density that increased following treatment, and non-responders (NR) with little immune cell presence before or after treatment.¹ Notably, radiotherapy served as an immune activating switch in R2 patients, converting immune-cold TMEs into environments where myeloid cells favorably interacted with T cells to promote anti-tumor activity.¹ CD4 and CD8 T cells with expression of CXCL13 strongly influenced communication with nearby myeloid cells to influence the efficacy of PD-L1 inhibitor treatment in TNBC patients.³ Higher baseline CXCL13 levels positively correlate with a pro-inflammatory macrophage phenotype and increased apoptotic signaling.³ Taken together, these studies underscore that identifying the immune composition of the TME prior to treatment may predict therapeutic response. Supporting these findings, it was shown that STAT1-high myeloid subsets generated by metronomic chemotherapy limit checkpoint blockade efficacy. Inhibiting STAT1 in this instance can reprogram myeloid cells to enhance anti-PD-1 targeting.⁴ To demonstrate this clinically, lutetium-based nanoparticles combined with a PARP inhibitor and low-dose radiation activates the cGAS-STING pathway promoting dendritic cell maturation and inducing immunological memory in TNBC tumor models.⁴ Similarly, alpha-ketoglutarate derivative DMKG in combination with anti PD-L1 inhibitors and radiotherapy suppressed tumor autophagy and encouraged tumor apoptosis by increasing CD8 T cell infiltration and increasing PD-L1 present on tumor cells allowing for precise targeting.²

Conclusions: Studies indicates that myeloid cell phenotype and TME organization are central to radioimmunotherapy response in TNBC. Personalized biomarker profiling, including assessment of CXCL13+ T cells, M1 versus M2 macrophage ratios, dendritic cell subsets, and STAT1-high myeloid populations, may offer a clinically actionable framework.⁵ This allows tailoring of radioimmunotherapy regimens to individual tumor immune landscapes, improving outcomes in this aggressive disease.

Works Cited:

1. Shiao SL, Gouin KH 3rd, Ing N, et al. Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer. Cancer Cell. 2024;42(1):70-84.e8. doi:10.1016/j.ccell.2023.12.012
2. Tan H, Liu J, Huang J, et al. Ketoglutaric acid can reprogram the immunophenotype of triple-negative breast cancer after radiotherapy and improve the therapeutic effect of anti-PD-L1. J Transl Med. 2023;21(1):462. Published 2023 Jul 12. doi:10.1186/s12967-023-04312-2
3. Palakurthi B, Fross SR, Guldner IH, et al. Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer. Nat Commun. 2023;14(1):2109. Published 2023 Apr 13. doi:10.1038/s41467-023-37727-y
4. Zeng B, Ling K, Yuan Q, et al. An organolutetium nanosensitizer synergizes with PARP inhibition to unleash STING-mediated immunity for low-dose radioimmunotherapy. Theranostics. 2026;16(4):1720-1739. Published 2026 Jan 1. doi:10.7150/thno.124034
5. Zhang Y, Chen H, Mo H, et al. Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer. Cancer Cell. 2021;39(12):1578-1593.e8. doi: 10.1016/j.ccell.2021.09.010
6. Malhotra MK, Emens LA. The evolving management of metastatic triple negative breast cancer. Seminars in Oncology. 2020;47(4):229. doi: 10.1053/j.seminoncol.2020.05.005.
7. Nelson MA, Ngamcherdtrakul W, Luoh S, Yantasee W. Prognostic and therapeutic role of tumor-infiltrating lymphocyte subtypes in breast cancer. Cancer Metastasis Rev. 2021;40(2):519. doi: 10.1007/s10555-021-09968-0.