An Injectable Epigenetic Autophagic Modulatory Hydrogel for Boosting Umbilical Cord Blood NK Cell Therapy Prevents Postsurgical Relapse of Triple‐Negative Breast Cancer

Triple‐negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a dismal prognosis. Umbilical cord blood natural killer (UCB‐NK) cell‐based immunotherapy represents a promising strategy for cancer treatment. However, its therapeutic efficacy is greatly restrained by downregulation of the NK cell activation ligand MHC class I‐related chain A/B (MICA/B) and autophagy‐mediated degradation of NK cell‐derived granzyme B (GZMB) in CSCs. Herein, it is demonstrated that suberoylanilide hydroxamic acid (SAHA) epigenetically downregulates let‐7e‐5p and miR‐615‐3p to increase MICA/B expression and that 3‐methyl adenine (3MA) inhibits autophagy‐mediated GZMB degradation, thereby sensitizing breast CSCs to UCB‐NK cells. Then, an injectable hydrogel is designed to codeliver SAHA and 3MA to enhance UCB‐NK cell infusion efficacy in TNBC. The hydrogel precursors can be smoothly injected into the tumor resection bed and form a stable gel in situ, allowing for a pH‐sensitive sustained release of SAHA and 3MA. Moreover, UCB‐NK cell infusion in combination with the hydrogel efficiently controls postsurgical relapse of TNBC. In addition, the hydrogel exhibits good hemostasis and wound‐healing functions. Therefore, the work provides proof of concept that an injectable epigenetic autophagic modulatory hydrogel augments UCB‐NK cell therapy to combat postsurgical relapse of TNBC. An injectable hydrogel for restoring major histocompatibility complex class I‐related chain A/B (MICA/B) expression and mitigating autophagic flux in breast cancer stem cells (BCSCs) is developed to enhance the efficacy of umbilical cord blood natural killer (UCB‐NK) cell infusion in combating postsurgical triple‐negative breast cancer (TNBC) relapse.