A new study published in Cancer Biology & Medicine has introduced a classification system for breast cancer based on the cancer-immunity cycle (CIC), offering a tool to predict patient response to immune checkpoint inhibitors and uncover new therapeutic targets. The research, conducted by scientists from Fudan University Shanghai Cancer Center and Shanghai Medical College, analyzed six key steps in the anti-tumor immune response to categorize tumors into three distinct subtypes with different immune profiles and vulnerabilities.
The cancer-immunity cycle describes the sequential process from cancer cell antigen release to T-cell-mediated killing. Defects in any step can render immunotherapies ineffective. The study, published with DOI 10.20892/j.issn.2095-3941.2025.0611, developed a “CIC score” to measure activity across these steps. Three clusters emerged: C1 (immune-cold), with low immune infiltration and poor prognosis; C3 (immune-hot), with high immune activity and best response to therapy; and C2, an intermediate subtype with a unique defect in antigen presentation despite high tumor mutational burden.
“The CIC provides a powerful framework for understanding how tumors evade the immune system,” the authors stated. “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.” The C2 subtype exhibited frequent HLA loss of heterozygosity and an immunosuppressive microenvironment enriched with dysfunctional dendritic cells and regulatory T cells. Multi-omic analyses revealed that C2 tumors depend on serine metabolism, with the enzyme PSAT1 identified as a key metabolic regulator. Knockdown of PSAT1 in cancer cells reduced expression of immunosuppressive molecules like PD-L1 and TGFB1.
This classification has immediate clinical implications. The CIC score could serve as a biomarker to stratify patients, identifying those likely to benefit from immunotherapy and sparing others from unnecessary side effects. Moreover, the distinct immune-evasion mechanisms point to novel combination therapies: for C1 tumors, strategies to convert the “cold” microenvironment into a “hot” one; for C2, enhancing antigen presentation by targeting PSAT1 or overcoming HLA loss. The study was supported by the National Key Research and Development Project of China and the National Natural Science Foundation of China.
