Amplifying the “in situ vaccination” of BET inhibition via autophagy blockade: mechanisms and local delivery in OSCC

Abstract

Oral squamous cell carcinoma (OSCC) remains a challenging malignancy with high recurrence and metastasis rates, often limited by insufficient immunogenicity and a suppressive tumor microenvironment. Immunogenic cell death (ICD) offers a promising approach to convert cell death into antitumor immunity; yet, its efficacy depends on precise modulation of autophagy and endoplasmic reticulum stress (ERS). Here, we report that combining the BET inhibitor JQ1 with the autophagy inhibitor chloroquine (CQ) synergistically amplifies ERS, leading to enhanced ICD in OSCC models. This combination promotes robust damage-associated molecular pattern (DAMP) release, dendritic cell activation, and antigen-specific CD8⁺ T-cell responses. To enable localized and efficient delivery, we engineered self-assembled JQ1/CQ nanoparticles stabilized through π–π stacking and integrated them into dissolvable cryomicroneedles. This minimally invasive platform ensures sustained drug release, improves tumor accumulation, and minimizes systemic exposure. Our study not only elucidates a druggable autophagy–ERS–ICD axis but also provides a versatile transdermal delivery strategy with potential applicability to a range of solid tumors.