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

Abstract

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.

IL-22 signaling promotes sorafenib resistance in hepatocellular carcinoma via STAT3/CD155 signaling axis

“…NK cells, as innate lymphocytes, are crucial in immune surveillance against cancer, particularly in preventing metastases due to their ability to recognize and kill cancer cells ( 40 – 42 ). It has been revealed that sorafenib can enhance NK cell antitumor immunity in HCC, which closely correlates with its therapeutic efficacy ( 43 ).…”

Recent advances in hydrogels for preventing tumor recurrence

“…137 In Gong et al 's report, the encapsulated mesoporous bioactive glass nanoparticles can generate abundant silanol groups at their external surface in aqueous solution. 138 These silanol groups interacted with amino groups to strengthen the crosslinking formed by Schiff's base bonds in the hydrogel. In addition, various stimuli-responsive injectable hydrogels have been developed.…”

“…A pH-responsive injectable hydrogel formed by the crosslinking of Schiff's base bonds was reported to co-deliver 3-methyl adenine and suberoylanilide hydroxamic acid (SAHA) to treat triple-negative breast cancer (TNBC). 138 When this hydrogel was injected into the surgical resection site, it could transform into a steady hydrogel in situ and achieve a pH-responsive continuous drug release to hinder the recurrence of TNBC after resection. In another study, Liu et al introduced UCNPs to construct an injectable and near-infrared (NIR)-light-responsive hydrogel with electrostatic interactions between UCNPs-Au and DNA (Fig.…”

“…191 Gong et al synthesized biocompatible mesoporous bioactive glass nanoparticles (MBGNs) and incorporated them into a gelatin-oxidized starch hydrogel. 138 MBGNs contained 15 mol% CaO and the release of Ca ions expedited fibroblast proliferation and epidermal regeneration. Hence, this hydrogel showed outstanding wound-healing functions in a TNBC mice model.…”

Biomaterial-Based Gene Delivery: Advanced Tools for Enhanced Cartilage Regeneration

“…One significant advantage of hydrogels is their tunable mechanical properties. 57 Through the regulation of polymer composition, crosslinking density, and formulation parameters, it is possible to customize the mechanical properties of hydrogels to align with the particular demands of the target tissue or application. This adaptability empowers hydrogels to replicate the mechanical attributes of natural tissues, promoting their integration and providing the necessary scaffolding for cellular growth and tissue regeneration.…”