Lanthanum Carbonate Nanosheets Based Colloidal Hydrogel for Modulating Innate & Adaptive Tumor Immunotherapy by Augmented Cellular Pyroptosis

Cellular pyroptosis, a pro‐inflammatory form of programmed cell death, emerges as a promising strategy for cancer immunotherapy. However, gene methylation hampers the expression of gasdermin E (GSDME), a pivotal protein in the caspase‐3‐mediated pyroptosis pathway, across numerous malignancies, including triple‐negative breast cancer (TNBC). This study elucidated that a colloidal hydrogel (GDLC hydrogel) loaded with decitabine (DAC) and crosslinked with lanthanum carbonate nanosheets (LCNSs) and gelatin nanoparticles (Gela NPs) could instigate pyroptosis in TNBC cells, specifically 4T1 cells. Within the tumor microenvironment (TME), the synergistic interaction between DAC and La 3+ reversed the epigenetic silencing of the GSDME gene, while concurrently activating caspase‐3, thus facilitating pyroptosis induction. Although monotherapy with La 3+ ‐induced apoptosis proved insufficient in tumor suppression, the concurrent inhibition of methyltransferase via DAC markedly suppressed both primary and recurrent tumors. Moreover, the combinatory application of the GDLC hydrogel and immune checkpoint inhibitors effectively neutralized the immunosuppressive TME of TNBC, triggered an anti‐tumor immune response and engendered a sustained immune memory effect. This strategy significantly curtailed tumor recurrence and metastasis, consequently improving the survival rates of mice in the 4T1 tumor‐bearing mouse model. In conclusion, this colloidal hydrogel platform introduced an innovative paradigm for the immunotherapy of triple‐negative breast cancer. The Gela/decitabine/La 2 (CO 3 ) 3 colloidal (GDLC) hydrogel developed here could reverse the epigenetic silencing of the GSDME gene by the synergistic interaction between DAC and La 3+ , while concurrently activating caspase‐3, thus facilitating pyroptosis induction under the tumor microenvironment. Moreover, the combinatory application of the GDLC hydrogel and immune checkpoint inhibitors effectively triggered robust anti‐tumor innate & adaptive immune responses and engendered a sustained immune memory effect.