Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00

Phosphorylation of the JNK (pJNK) protein promotes an immunosuppressive tumor microenvironment (TME), enhancing aggressiveness in inflammatory triple-negative breast cancer (TNBC). This study evaluated the role of JNK signaling using a gene signature. RNA sequencing was performed on 347 TNBC tumors from the phase 3 International Breast Cancer Study Group (IBCSG) 22-00 trial, which evaluated adjuvant low-dose cyclophosphamide and methotrexate (CM). Immune-related tumors were identified by TNBC subtype or tumor-infiltrating lymphocytes (TILs). Associations between JNK and outcomes were analyzed using Cox models. Low pJNK levels were associated with better disease-free survival (DFS) in immune-related tumors. These tumors also had lower Treg levels and higher CD8⁺/Treg ratios. Notably, immunomodulatory (IM) tumors with high pJNK showed improved DFS when treated with CM. High pJNK expression identifies immunosuppressive TMEs with poor prognosis in inflamed TNBC. However, these tumors may benefit from CM, supporting pJNK as a potential biomarker for immunotherapy strategies.