Editor’s Note: Immunotherapy has become an important treatment modality in breast cancer, achieving breakthroughs by modulating the immune system to mount anti-tumor responses. At the 8th Conference on Oncology Precision Medicine and the 11th Conference on Individualized Therapy for Breast Cancer held in Beijing, Professor Fei Ma of the Cancer Hospital, Chinese Academy of Medical Sciences, delivered a presentation on “Clinical Exploration of Breast Cancer Immunotherapy,” reviewing the current status, challenges, and future directions. Following her talk, Oncology Frontier invited Professor Ma to discuss the synergistic mechanisms of immunotherapy combined with metronomic chemotherapy, strategies for monitoring and managing immune-related adverse events, and biomarker-driven precision treatment pathways.Synergistic Mechanisms of Metronomic Chemotherapy with Immunotherapy
Oncology Frontier:Your team’s phase II prospective randomized study suggested significant differences in synergy between immunotherapy and various chemotherapy regimens. Mechanistically, how does metronomic chemotherapy reshape the tumor microenvironment to enhance immunotherapy efficacy?
Professor Fei Ma:Traditionally, metronomic chemotherapy was referred to as “anti-angiogenic chemotherapy,” but we have also long suspected it has immune-modulating properties. Metronomic chemotherapy involves administering relatively low doses of cytotoxic drugs at high frequency over a sustained period, with relatively mild toxicity compared with conventional high-dose regimens.
When combined with immunotherapy, our results demonstrated that metronomic chemotherapy could actually produce stronger synergistic effects than high-dose chemotherapy combinations.
Mechanistically, there are several possible explanations:
- Microenvironment regulation. Metronomic chemotherapy reduces regulatory T cells (Tregs) and delays their exhaustion, which promotes local immune responses—unlike conventional chemotherapy.
- Systemic immune reprogramming. It may reshape host immunity, steering it toward improved responsiveness to immunotherapy.
- Vascular normalization. By inhibiting endothelial cells, it helps normalize tumor vasculature, which in turn enhances immune response.
Beyond these, other mechanisms may exist, and we are continuing to investigate them.
Immune-Related Adverse Events: Monitoring and Intervention
Oncology Frontier:While immunotherapy has brought survival benefits in TNBC, resistance remains an issue. What adverse events do you most often encounter in clinical practice, and how should they be monitored and managed?
Professor Fei Ma:Although immunotherapy has improved outcomes in triple-negative breast cancer, adverse events (AEs) remain a major concern, affecting both clinical decision-making and patient adherence.
Immune-related AEs fall into two broad categories:
- More common, generally mild events such as rash and thyroid dysfunction. These can be managed with close observation, dose modification, or local treatment, without necessarily discontinuing therapy.
- Less common but potentially life-threatening events, such as immune-mediated myocarditis, pneumonitis, or encephalitis.
Clinical management requires several steps:
- Baseline screening. Before starting therapy, we assess comorbidities such as cardiovascular or pulmonary disease to identify patients at higher risk.
- Close monitoring. During treatment, we monitor both biomarkers and symptoms to detect AEs at the earliest possible stage.
- Timely intervention. Early recognition and treatment are crucial to minimizing harm.
In the future, novel companion diagnostics may enable even earlier detection of serious immune-related AEs, which is an important direction for ongoing research.
Biomarker-Driven Precision Immunotherapy
Oncology Frontier: With new immunotherapies emerging, how can biomarkers such as TMB and PD-L1 expression guide the development of novel combination strategies to achieve synergistic “1+1>2” effects?
Professor Fei Ma:Immunotherapy is now widely applied across many tumor types and at multiple disease stages, often in combination with other strategies. However, the definition of the “ideal responder population” remains unsettled.
Different companion diagnostics are used in different contexts: CPS scoring for PD-L1 in some tumors, TPS scoring in others, and in some cases, no companion testing is required. Even within the same tumor type, definitions of benefit populations vary depending on disease stage and trial design.
To refine patient selection, we must start with a deeper understanding of immunotherapy’s mechanisms. Unlike chemotherapy or targeted therapy, which act directly on tumor cells, immunotherapy targets immune effector cells, and its efficacy is shaped by tumor characteristics, the immune microenvironment, and host systemic immunity. We have even observed that gut microbiota composition can influence treatment outcomes.
Thus, the future of companion diagnostics in immunotherapy will not rely on a single biomarker but rather on multifactorial models built on large datasets and novel algorithms. Such integrated biological models will be essential to achieve true precision in immunotherapy.
Professor Fei Ma
Chief Physician, Professor, Doctoral SupervisorChangjiang Scholar Distinguished ProfessorDirector, Department of Medical OncologyNational Cancer Center / Cancer Hospital, Chinese Academy of Medical Sciences
