Natural phenolic acid-based self-assembly promotes anti-tumor immune amplification by ATP-ADO axis regulation and its spiky structure.

The integration of bioactive micro-nano drug carrier components with rational design of morphological structures is poised to address the therapeutic challenge in anti-tumor immunotherapy focusing on immunogenic cell death (ICD). In this article, based on ATP-adenosine (ADO) axis regulation induced by ellagic acid (EA), the spiky self-assembly (EZ) was tailored with EA and Zn2+, and next engineered to construct ATP and pH dual-responsive EZ@MTPP for anti-tumor immune amplification. Following intratumoral injection, the spiky structure of EZ@MTPP enabled efficient local retention, then the ATP-sensitive spines of EZ slowly discharged EA and Zn2+ while scavenging ATP. EA silenced the ATP-ADO pathway, lowering immunosuppressive ADO and PD-L1 levels, and Zn2+ activated the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) stimulator of interferon genes (STING) signaling pathway cascade and downstream immunity. Concomitantly, acidification of the TME triggered detachment of microwave-induced tumor-derived microparticles loaded with paclitaxel (MTPP) from EZ, which were acquired by neighboring tumor cells to release paclitaxel (PTX) to elicit apoptosis and robust ICD. After coupling the spiky EA-based self-assembly with PTX-loaded MTPP, EZ@MTPP MPs eradicated tumor cells, relieved ADO-mediated immunosuppression and amplified ICD-driven immunity by components and morphological structures co-facilitation, offering an innovative paradigm for metabolism-focused cancer immunotherapy.