Programmable local immunochemotherapy for triple-negative breast cancer via spatiotemporally controlled release of CpG oligodeoxynucleotides, gemcitabine, and paclitaxel.

Triple-negative breast cancer (TNBC) remains a highly aggressive subtype with limited targeted treatment options and substantial toxicity from systemic chemoimmunotherapy. We developed a Programmable Local Immunochemotherapy (PLICT) platform integrating a CpG oligodeoxynucleotide (CpG ODN)/gemcitabine-loaded hydrogel for rapid release and paclitaxel-loaded PLGA microspheres for sustained delivery. In a TNBC mouse model, peritumoral administration of PLICT enabled sequential release, facilitating the local delivery of immune agonist and chemotherapy to suppress early tumor growth, followed by prolonged inhibition of tumor progression and metastasis. Compared to systemic chemotherapy, PLICT significantly enhanced intratumoral cytotoxic T lymphocyte infiltration and favorably modulated the local immune microenvironment with minimal systemic toxicity. These findings highlight the therapeutic potential of PLICT as a locally administered, immune-potentiating strategy for effective TNBC treatment.