Background <p>Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression, leading to poor clinical outcomes and resistance to targeted therapies. Immunotherapy has shown limited success due to the development of resistance mechanisms. This study aimed to investigate the role of long non-coding RNA LINC02544 in mediating immunotherapy resistance through regulation of the miR-497-5p/CAPRIN1 axis in TNBC.</p> Methods <p>Bioinformatic analyses of TCGA and GEO databases were performed to assess LINC02544 and miR-497-5p expression in TNBC tissues. In vitro experiments evaluated the regulatory effects of LINC02544 on miR-497-5p and CAPRIN1 expression, as well as TNBC cell proliferation and migration. Exosome-mediated siRNA delivery targeting LINC02544 (exo/si-LINC02544) was tested both in vitro and in vivo in combination with a PD-1 inhibitor in a TNBC mouse model.</p> Results <p>LINC02544 was significantly overexpressed in TNBC, while miR-497-5p was downregulated. In vitro, LINC02544 silencing via exo/si-LINC02544 reduced CAPRIN1 levels, upregulated miR-497-5p, and inhibited TNBC cell proliferation and migration. In vivo, exo/si-LINC02544 combined with PD-1 blockade suppressed tumor growth and enhanced immune cell infiltration.</p> Conclusions <p>Targeting the LINC02544/miR-497-5p/CAPRIN1 axis with exosome-based siRNA delivery represents a promising therapeutic strategy to overcome immunotherapy resistance in TNBC.</p>