New Breakthrough in Precision Treatment of Triple-Negative Breast Cancer: Bridging Basic and Clinical Research, Mast Cells Reverse Resistance to Immunotherapy
Breast cancer is currently the most common malignant tumor among women worldwide. Among them, triple-negative breast cancer, which accounts for about 15% of the total breast cancer population, is known as the most "aggressive" breast cancer due to its high degree of malignancy and short patient survival time. Immunotherapy, represented by PD-1 inhibitors, has become an important treatment for triple-negative breast cancer. However, more than 50% of patients will develop immunotherapy resistance. How can these drug-resistant patients benefit from immunotherapy? Related areas require in-depth research.
On June 25, 2025, the team of Professor Shao Zhimin and Professor Jiang Yizhou from the Breast Surgery Department of Fudan University Shanghai Cancer Center published a paper in the internationally renowned academic journal Nature Medicine. The findings showed that based on AI technology, the team integrated multi-modal information from 528 triple-negative breast cancer patients, and for the first time identified atypical antigen-presenting mast cells (apMC) as a key factor in the effectiveness of anti-PD-1 immunotherapy. It can activate tumor-reactive T cells and promote anti-tumor immune responses.
The research team also found that cromolyn sodium, a commonly used clinical anti-allergic drug, can induce antigen-presenting mast cells, thereby reversing immunotherapy resistance in tumor patients. Based on this, the team built the world's first clinical research platform for reversing immunotherapy resistance in breast cancer - "Renaissance", and carried out clinical research on the innovative targeted immunotherapy strategy of "cromoglycate sodium + immunotherapy" for patients with metastatic triple-negative breast cancer who were previously resistant to immunotherapy and had almost no further treatment options. The results show that the treatment effectiveness of patients using this innovative target immune regimen has increased significantly from about 10% in the past to 50%.
Shao Zhimin said that this study targets the pain points of immunotherapy resistance in triple-negative breast cancer patients, focuses on the tumor microenvironment, explores and analyzes the molecular mechanisms of drug resistance, and then improves the "clinical-basic-clinical" "reverse translational" research model, discovers the key "code" to solve clinical problems, opens up the research "barrier" from molecular mechanisms to clinical translation, and provides new hope for precision treatment of triple-negative breast cancer patients who are "incurable" after immunotherapy resistance.
Filling the gap in research on immunotherapy resistance in the most "aggressive" breast cancer: identification of previously neglected antigen-presenting mast cells for the first time
Shao Zhimin introduced that tumor ecology is of great significance to the molecular biological behavior and treatment response of tumors. The microenvironment of triple-negative breast cancer is more complex than that of other subtypes of breast cancer, making it more difficult to formulate treatment strategies. Research on resistance to anti-PD-1 immunotherapy is an important challenge in the treatment of triple-negative breast cancer.
Mast cells are a type of human immune cells. They are mainly located in the body's barrier tissues such as mucous membranes and play important immune regulatory functions. Previous studies have found that the characteristics of mast cells vary greatly in different tumors, and even in the same tumor, there are obviously different phenotypes. In the field of triple-negative breast cancer research, are mast cells involved in tumor progression, do they affect tumor immune escape, and how to intervene to reverse immunotherapy resistance? So far, no research has elucidated in depth.
Based on this thinking, the research team of Shao Zhimin and Jiang Yizhou combined AI technology and multi-modal data analysis to integrate multi-dimensional information from patients in Asia, Europe and the United States to build the first high-resolution detection cohort of newly treated triple-negative breast cancer that matches the efficacy of immunotherapy, avoid bias caused by differences in previous treatments and tumor metastasis, and achieve accurate identification of the complex regulatory network of the breast tumor microenvironment.
The study found that triple-negative breast cancer mast cells have significant systemic heterogeneity and phenotypic plasticity, and for the first time revealed that they stably exist in three independent functional states in different populations: vigorous metabolism, sensitization activation, and antigen presentation; among them, the level of mast cell infiltration in the antigen presentation state is significantly related to the clinical benefit of anti-PD-1 immunotherapy.
To further explore this mechanism, the research team found through precise analysis of cell spatial positioning that antigen-presenting mast cells are significantly enriched in the tertiary lymphoid structure of the triple-negative breast cancer microenvironment and have close spatial interactions with tumor-characteristic responsive T cells. At the same time, antigen-presenting mast cells express key functional molecules of the antigen presentation pathway such as MHC-II, CD40, CD80, CD86, and IL-12. The gold standard in vitro research models of antigen presentation, OT-II and OT-I, further confirm that antigen-presenting mast cells can perform the full chain of functions of antigen phagocytosis, processing, and presentation, and activate tumor-specific reactive T cells.
Furthermore, the research team constructed a gold standard in vivo model for cell research using Cpa3CreERT2Cd74fl/fl conditional gene knockout experimental animals and mice, consolidating the positive feedback pathway of triple-negative breast cancer "mast cells-CD74-tumor-responsive T cells-tertiary lymphoid structures" to drive the body's precise immune killing of tumor cells.
The treatment effectiveness of drug-resistant patients has been greatly improved: the commonly used anti-allergic drug cromoglycate sodium reverses the dilemma of immunotherapy resistance
In order to explore the value of targeted therapy of antigen-presenting mast cells, the research team conducted in-depth exploration. After fully demonstrating the immune activation potential of this type of cells, the research team included 484 patients with triple-negative breast cancer and found that baseline tumor antigen-presenting mast cell infiltration was an independent predictor of benefit from anti-PD-1 immunotherapy for both primary and metastatic patients.
Subsequently, the team noticed that compared with other mast cell subpopulations, antigen-presenting mast cells showed weaker allergic phenotypes and later cell development. Combining 6 mouse models and more than 100 human patient organoid mixed culture models, they conducted parallel and repeated demonstrations on two experimental platforms with genetic backgrounds. They found that sodium cromoglycate, a commonly used clinical anti-allergic drug, has potential application value in promoting the function of antigen-presenting mast cells and reversing resistance to immunotherapy. Based on this, the research team launched the "Renaissance" clinical research platform.
Among the patients included in this study, 100% had received immunotherapy, 100% had received taxane chemotherapy drugs, 90% had received anti-vascular targeted therapy, 40% had more than 3 metastases, and 30% had received more than 2 lines of treatment. Currently, it is considered to be almost "incurable" in clinical practice. In various clinical trials conducted in the past, the effective rate of such patients receiving later-line treatment was only about 10%; however, the objective tumor response rate of the target-immune combination regimen combined with cromoglycate sodium was as high as 50%, and the treatment effective rate was increased by nearly 4 times. Moreover, the safety of this combination regimen is controllable, no new adverse reactions have been observed, and safe clinical management can be achieved.
"It often takes tens of years to develop drugs that can be used in actual clinical applications for potential innovative molecules or inhibitors," Jiang Yizhou said. "Under the current long-cycle drug research and development chain, on the basis of clarifying the molecular mechanism of tumor resistance, using existing drugs to create a 'combination punch' is the most economical and efficient solution in clinical practice. The 'Fuxing' platform is The core purpose of the world's first new drug/new regimen application platform for patients with immunotherapy-resistant triple-negative breast cancer is to clinically transform treatment strategies with innovative application potential discovered in basic research, so as to truly benefit patients. In the study, the cromoglycate sodium combination treatment regimen has achieved promising results, and is expected to be rapidly used in clinical applications."
Build a translational research platform for breast cancer with Chinese characteristics: Promote the development and application of new drugs, new technologies, and new solutions
It is understood that the team led by Shao Zhimin began to work on solving the problem of precise treatment of triple-negative breast cancer more than ten years ago. Independently developed and established a "multi-gene prognostic model" for triple-negative breast cancer; established the world's largest multi-omics cohort of triple-negative breast cancer, drew the world's largest genetic map of triple-negative breast cancer, and pioneered a "precision treatment strategy for triple-negative breast cancer based on the 'Fudan four-subtype classification'"...
In a series of clinical trials such as FUTURE, FUTURE-SUPER, BCTOP-A-01, and CamRelief carried out on this basis, the research team used new ideas and new targets discovered in basic research to achieve preliminary exploration of new solutions from basic to clinical, and built a Chinese-specific breast cancer translational research platform to promote the research and development of new drugs and new technologies; the treatment efficiency of first-line treatment for patients with metastatic triple-negative breast cancer was increased to 81.3%, the highest in the world during the same period.
The innovation of the "reverse translational" research model for triple-negative breast cancer and the establishment of the "Renaissance" research platform will break down the barriers between previous basic research and clinical application, and further guide the clinical practice of precision immunotherapy for triple-negative breast cancer.
Shao Zhimin said that the cancer hospital also took the lead in establishing the Breast Cancer Precision Treatment Collaboration Group (BCTOP), which aims to collaborate in multi-center clinical research on precision treatment of breast cancer, promote the integration of medicine and industry, and build a breast cancer translational research platform with Chinese characteristics. It is expected that more Chinese original solutions will be produced to benefit breast cancer patients around the world.
Wu Songyang, Jin hope, and Liu Yin from the Department of Breast Surgery at Fudan University Shanghai Cancer Center are the co-first authors of this paper, and Shao Zhimin and Jiang Yizhou are the co-corresponding authors.