A new study published in Cancer Biology & Medicine has developed a framework to classify breast cancer based on the cancer-immunity cycle (CIC), potentially improving prediction of patient response to immunotherapy. The research, conducted by scientists from Fudan University Shanghai Cancer Center and Shanghai Medical College, analyzed six key steps of the CIC to create a scoring system that categorizes breast tumors into three subtypes, each with distinct immune profiles and vulnerabilities.
The cancer-immunity cycle describes the sequential steps required for an effective anti-tumor immune response, from antigen release to T-cell killing. Defects at any stage can render immunotherapies like immune checkpoint inhibitors (ICIs) ineffective. By integrating transcriptomic data, the team calculated a CIC score for each step and identified three clusters: C1 (immune-cold), C2 (intermediate with antigen presentation defects), and C3 (immune-hot). C1 tumors showed low immune infiltration and poor prognosis, while C3 tumors exhibited high T-cell activity and best ICI response. The C2 subtype was particularly notable—despite high tumor mutational burden, these tumors had frequent HLA loss of heterozygosity and an immunosuppressive microenvironment enriched with dysfunctional dendritic cells and regulatory T cells.
Multi-omic analyses revealed metabolic dependencies unique to each cluster. C1 tumors were enriched in sphingolipid metabolism, while C2 tumors relied heavily on serine metabolism. The enzyme PSAT1 emerged as a key regulator in C2; its knockdown reduced expression of immunosuppressive molecules like PD-L1 and TGFB1. The authors stated that the CIC framework allows identification of specific, actionable defects beyond the simple hot/cold tumor paradigm. This could guide combination therapies: converting cold tumors to hot for C1, or enhancing antigen presentation for C2 by targeting PSAT1 or overcoming HLA loss.
The study provides a robust biomarker, the CIC score, for stratifying patients and selecting those likely to benefit from ICIs while avoiding unnecessary side effects for others. The findings also open avenues for novel combination strategies tailored to each subtype. The research was supported by the National Key Research and Development Project of China and the National Natural Science Foundation of China. The full study is available at https://doi.org/10.20892/j.issn.2095-3941.2025.0611.
