MAL/SPP1 axis drives tumor proliferation and immune evasion via JAK2/STAT3 and MHC class Ib in breast cancer

Breast cancer persists as the second leading cause of cancer-related mortality in women globally. Identifying key molecular drivers governing tumor growth and invasion could substantially improve diagnostic precision and therapeutic outcomes. This study employed 4T1 triple-negative breast cancer cells (TNBC) to establish a clinically relevant sequential metastasis model. Using this model, we identified a progressive upregulation of myelin and lymphocyte protein (MAL) expression, which demonstrated a strong positive correlation with breast cancer growth and progression. Integrated methodologies-combining transcriptomic sequencing, functional cellular assays, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-mediated gene knockout, and in vivo intervention studies-revealed MAL's dual oncogenic function in promoting both primary tumor growth and metastatic spread. Mechanistically, MAL drives tumorigenesis by upregulating secreted phosphoprotein 1 (SPP1), thereby activating the Janus Kinase 2-Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling axis to stimulate angiogenesis and accelerate proliferation. Simultaneously, it subverts anti-tumor immunity by exploiting major histocompatibility complex (MHC) class Ib molecules, suppressing T-cell infiltration and impairing CD8⁺ T-cell tumor-lytic activity within the tumor microenvironment. Critically, targeted inhibition of MAL effectively curtailed breast cancer progression, underscoring its promise as a novel therapeutic target for metastatic breast cancer intervention.