Targeting RAB27A Enhances Pembrolizumab Sensitivity and Alleviates Immune Escape via Inactivation of the PI3K /Akt/ mTOR Pathway in Triple‐Negative Breast Cancer

Ras‐related protein Rab‐27A (RAB27A) is involved in tumour progression and immune regulation. This study investigated its role in triple‐negative breast cancer (TNBC) progression, immune escape and responsiveness to immune checkpoint inhibitors. RAB27A expression was analysed in TNBC tissues and public datasets. Gain‐ and loss‐of‐function experiments were performed in TNBC cells. Peripheral blood mononuclear cell (PBMC)‐based tumour coculture systems and xenograft mouse models were used to evaluate antitumor immunity and therapeutic responses. RAB27A was upregulated in TNBC and correlated with chemotherapy resistance, advanced T stage, high Ki‐67 expression and CD8 + T‐cell infiltration. RAB27A overexpression activated PI3K/Akt/mTOR signalling and promoted tumour cell migration and invasion, whereas RAB27A silencing had the opposite effects. Combined RAB27A targeting and PI3K inhibition decreased PD‐L1 expression and cell viability while increasing HLA‐I expression and apoptosis; these effects were further enhanced by pembrolizumab. In PBMC coculture models, combination treatment promoted T‐cell proliferation and CD8 + T‐cell expansion while suppressing malignant phenotypes. In vivo, RAB27A knockdown inhibited tumour growth, reduced PI3K/Akt/mTOR activation and PD‐L1 expression and increased HLA‐I expression. Targeting RAB27A enhances antitumor immunity and pembrolizumab sensitivity by blocking the PI3K/Akt/mTOR axis, representing a potential strategy to overcome immune resistance in TNBC.