Carboxymethyl cellulose-based injectable hydrogel as co-delivery platform for doxorubicin and decitabine: Inducing pyroptosis and enhancing immunotherapy in breast cancer

Abstract

Despite remarkable advances in breast cancer treatment, conventional chemotherapy still faces major challenges, including insufficient drug accumulation at the tumor site, severe systemic toxicity, and limited immune induction. To overcome these challenges, we developed an injectable carboxymethyl cellulose (CMC)-based hydrogel for the localized co-delivery of doxorubicin (DOX) and decitabine (DAC). Beyond conventional drug delivery hydrogels, this CMC-based hydrogel exhibited an optimal gelation time, favorable physicochemical properties, porous three-dimensional microstructures, excellent biocompatibility, and ideal sustained drug-release capability. Notably, the DAC+DOX/Gel system could synergistically induce pyroptosis through the caspase-3/GSDME pathway, with a ∼26-fold increase in the pyroptosis index compared to free drugs. The HMGB1 secretion and CRT exposure suggested the induction of immunogenic cell death and the potential for anti-tumor immune activation. Furthermore, in vivo evaluation in 4T1 tumor-bearing mice demonstrated superior anti-tumor effects and inhibition of distant metastasis. Importantly, this platform significantly enhanced tumor-specific T cell immunity and promoted localized immune activation within the tumor microenvironment without triggering systemic inflammatory responses. Therefore, this bioengineered hydrogel represents a breakthrough in localized combination therapy that simultaneously overcomes drug delivery challenges and transforms immunologically "cold" tumors through pyroptosis-mediated immune activation, offering a promising therapeutic strategy for chemo-immunotherapy of breast cancer.

Keywords: Breast cancer; Carboxymethyl cellulose; Immunotherapy; Injectable hydrogel; Pyroptosis.