On February 7, 2025, the research team led by Prof. Zemin Zhang at the Peking University Biomedical Pioneering Innovation Center (BIOPIC), in collaboration with the team in National Cancer Center / Cancer Hospital Chinese Academy of Medical Sciences, published an article titled “Distinct Cellular Mechanisms Underlie Chemotherapies and PD-L1 Blockade Combinations in Triple-Negative Breast Cancer” in Cancer Cell.

 

 

Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer. Due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, patients with TNBC are ineligible for hormone therapy or HER2-targeted therapies. Traditional chemotherapy for TNBC patients offers only transient benefits, highlighting the urgent need to develop more effective treatments, which is a key focus in current breast cancer research. Immunotherapy, notably immune checkpoint blockade (ICB), has revolutionized cancer treatment. However, the unique tumor immune microenvironment (TIME) of TNBC limits the efficacy of monotherapy.

 

Although chemotherapy combined with immune therapy has shown promising synergistic effects in clinical settings, the molecular mechanisms behind this combination remain unclear. On October 14, 2021, the team led by Zemin Zhang from Peking University, in collaboration with the current research team, published a study titled “Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer” in Cancer Cell. This work systematically characterized tumor and peripheral blood immune cells in TNBC patients treated with paclitaxel (PTX) and its combination with anti-PD-L1 therapy at single-cell resolution, elucidating the dynamics of TIME under different regimens and uncovering the mechanisms underlying the synergy between anti-PD-L1 and PTX in TNBC.

 

Figure 1. Research strategy and key findings

 

The current study extends prior work by integrating published and newly generated single-cell RNA sequencing (scRNA-seq) data from TNBC patients treated with paclitaxel (PTX), nab-paclitaxel (Nab-PTX), and their combinations with the anti-PD-L1 antibody atezolizumab (ATZ). This comprehensive analysis deciphers the distinct cellular mechanisms by which different chemotherapies modulate TIME, either antagonizing or synergizing with ICB. Notably, the study suggests mast cells as a promising adjunct for enhancing ICB therapy efficacy, providing a theoretical foundation for optimizing precision therapy in TNBC.

 

A key finding is that Nab-PTX combined with atezolizumab exhibits superior immunomodulatory effects compared to PTX. ATZ plus Nab-PTX rewires TCF7+ stem-like effector memory CD8+ T cells (Tsem) and CD4+ T follicular helper (Tfh) cells. These T cell subsets are considered key drivers of anti-tumor immune responses, capable of supporting long-term tumor immune surveillance and cytotoxic activity. Furthermore, Nab-PTX reshapes the myeloid compartment differently compared to PTX, expanding mast cells and pro-inflammatory macrophages (such as Macro-CXCL9, Macro-FOLR2, Macro-CCL3L1, etc.), thereby amplifying localized immune activation. This finding elucidates the unique immunomodulatory effects of Nab-PTX and provides a scientific basis for selecting chemotherapeutic agents.

 

Figure 2. Synergistic mechanism of Nab-PTX therapy combined with PD-L1 blockade

 

Another pivotal discovery underscores the crucial role of mast cells in orchestrating anti-tumor immune responses, likely by promoting the recruitment and activation of T and B cells and activating the local immune milieu. In vivo experiments demonstrate that mast cell activation in combination with anti-PD-L1 led to tumor suppression, comparable to the effect of Nab-PTX+ATZ. This combinatorial approach remodels the TIME and enhances tumor immunogenicity, surpassing monotherapy efficacy.

 

This study elucidates the mechanistic divergence between PTX and Nab-PTX when combined with ICB, highlighting the critical role of chemotherapy selection in combinatorial regimens. These findings hold substantial clinical significance for TNBC and other malignancies, informing the optimization of therapeutic strategies. Contrary to the traditional view of mast cells as pro-tumorigenic components, this study redefines their role as “orchestrators” of anti-tumor immunity under specific therapeutic condition, which enhance ICB efficacy by promoting functional activation of T and B cells. Further research is needed to fully understand the roles of mast cells across cancer types, yet this discovery highlights their potential as a therapeutic target to enhance immunotherapy, laying the groundwork for drug development and clinical trial design.

 

Collectively, this study elucidates the distinct mechanisms through which chemotherapy and immunotherapy synergize in TNBC at molecular, cellular, and systemic levels. It contributes to the theoretical foundation of clinical therapeutic strategies while providing a novel paradigm for mast cell functions.

 

Paper link: https://doi.org/10.1016/j.ccell.2025.01.007

 

Academician Zemin Zhang (BIOPIC, Peking University), Prof. Fei Ma, Prof. Zhihua Liu, Academician Binghe Xu and Dr. Yuanyuan Zhang (Chinese Academy of Medical Sciences and Peking Union Medical College) are co-corresponding authors. Dr. Yuanyuan Zhang, Dr. Hongyan Chen, Dr. Hongnan Mo, and Dr. Ning Zhao are co-first authors. The research was supported by the National Key Research and Development Program, the National Natural Science Foundation, and the CAMS Innovation Fund for Medical Sciences.