Editor’s Note: A deep understanding of the dynamic changes within the tumor microenvironment is crucial to accurately assess treatment response and disease progression in cancer patients. At the 2025 ASCO Annual Meeting, Professor Jieqiong Liu and her team from Sun Yat-sen Memorial Hospital, Sun Yat-sen University, presented an innovative study in the field of metastatic breast cancer treatment (Abstract #1022).This study focused on the efficacy and safety of the combination therapy KN046 and KN026 in patients with HER2-positive breast cancer who had failed second-line or later treatments. Using single-cell sequencing technology, the team analyzed tumor microenvironment changes before and after treatment.
The findings revealed significant differences in the immune microenvironment between treatment-sensitive and treatment-resistant patients. Notably, the baseline Mϕ/LEC (macrophage/lymphatic endothelial cell) ratio was identified as a potential predictive biomarker for treatment efficacy. These insights offer a promising new direction for personalized, precision therapy in breast cancer.
1022-Longitudinal tissue analysis and correlation of microenvironmental changes with combined immunotherapy and targeted therapy response in metastatic breast cancer.
Researcher’s Commentary Targeted anti-HER2 therapy combined with chemotherapy has improved survival outcomes in patients with metastatic HER2-positive breast cancer. However, for those who experience disease progression after such treatments—particularly after multiple lines of therapy involving tyrosine kinase inhibitors (TKIs) or antibody-drug conjugates (ADCs)—therapeutic options remain limited.
To address this need, we conducted a multicenter, single-arm Phase II clinical trial evaluating the efficacy and safety of the combination therapy of KN046 and KN026 in patients with advanced HER2-positive breast cancer who had progressed after prior anti-HER2 chemotherapy or ADC treatment. The results of this study were published in Clinical Cancer Research in April of this year. The chemotherapy-free regimen combining targeted therapy and immunotherapy achieved an objective response rate (ORR) of 47.2%, with a low incidence of grade 3/4 toxicities, offering a new treatment option for this patient population.
However, we also observed that at least half of the patients developed resistance to treatment. In order to identify patients most likely to benefit from this regimen—and to advance individualized and precise cancer care—we performed single-cell RNA sequencing and T cell receptor sequencing on tumor samples collected before and after treatment from a subset of enrolled patients. The analysis revealed significant time-dependent changes in the composition and phenotypes of immune cell populations within the TME, closely associated with treatment sensitivity. These results illuminate the dynamic immune microenvironment alterations driven by targeted immunotherapy and help uncover the molecular mechanisms underlying resistance. The baseline Mϕ/LEC ratio emerged as a promising biomarker to distinguish between responders and non-responders, potentially guiding the future development of more effective, personalized treatment strategies.
Lastly, we extend our sincere gratitude to Professor Jianyou Liao from Sun Yat-sen Memorial Hospital and Professor Chuangui Song from Fujian Cancer Hospital for their invaluable support and contributions to this study.
Chief Physician, Department of Breast Surgery Doctoral Supervisor, Sun Yat-sen Memorial Hospital, Sun Yat-sen University
Deputy Director, Department of Breast Diagnostics, Breast Center, Sun Yat-sen Memorial Hospital 8th “Yangcheng Outstanding Physician” Awardee Guangdong Provincial Outstanding Young Medical Talent
Youth Committee Member, Breast Cancer Group, Chinese Medical Association Oncology Branch Committee Member, CSCO Translational Medicine Subcommittee Committee Member, Tumor Metastasis Committee, Chinese Anti-Cancer Association Young Scholar, Breast Cancer Committee, Chinese Anti-Cancer Association Member, Surface Tumor Group, Committee of Reconstructive Surgery, Chinese Association of Rehabilitation Medicine Standing Committee Member, Specialty Committee, Chinese Medical Women’s Association
Second Prize, Guangdong Provincial Science and Technology Progress Award (First Author) Joint PhD Training at Massachusetts General Hospital, Harvard University (2008–2010) Postdoctoral Fellowship at the Breast Center, Johns Hopkins Hospital (2014–2015)
Professor Liu has published over 40 SCI-indexed papers as first or corresponding author in journals such as PNAS, Clinical Cancer Research (CCR), Journal for ImmunoTherapy of Cancer (JITC), and Nature Communications (NC). She has also led 13 scientific research projects.
