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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.