A study published in Cancer Biology & Medicine introduces a novel classification system for breast cancer based on the cancer-immunity cycle (CIC), offering a comprehensive approach to predict patient response to immune checkpoint inhibitors (ICIs) and identify new therapeutic targets.
The cancer-immunity cycle maps the step-by-step process of the anti-tumor immune response. Defects in any step can halt the cycle and render immunotherapy ineffective. Researchers from Fudan University Shanghai Cancer Center and Shanghai Medical College developed a 'CIC score' measuring activity of six key steps. Analyzing these scores across breast cancer patients, they identified three distinct clusters: C1 ('immune-cold'), C2 (intermediate with antigen presentation defects), and C3 ('immune-hot').
C1 tumors showed low immune infiltration, poor prognosis, and abundance of immunosuppressive M2 macrophages. C3 tumors exhibited high immune cell infiltration, active T cells, and best response to ICI therapy. The most unexpected finding was C2: 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 specific metabolic dependencies: C1 enriched in sphingolipid metabolism, C2 dependent on serine metabolism. The enzyme PSAT1 was identified as a key metabolic regulator in C2; its knockdown reduced expression of immunosuppressive molecules like PD-L1 and TGFB1.
'The CIC provides a powerful framework for understanding how tumors evade the immune system,' the authors said. 'By building a comprehensive score that captures the efficiency of this entire cycle, we've moved beyond the simple hot and cold tumor paradigm to identify distinct, actionable defects.'
This classification has immediate clinical implications. The CIC score could stratify patients to identify those likely to respond to ICIs, sparing others from side effects. Moreover, discovering distinct immune-evasion mechanisms paves the way for novel combination therapies: for C1, converting the cold microenvironment; for C2, enhancing antigen presentation by targeting PSAT1 or overcoming HLA loss.
The study was published in Cancer Biology & Medicine (DOI: 10.20892/j.issn.2095-3941.2025.0611). The journal is sponsored by China Anti-cancer Association and Tianjin Medical University Cancer Institute & Hospital, and is indexed in SCOPUS, MEDLINE and SCI (IF 12.4).
