Tumor-permeated ATP-based size-controllable immunogenic cell death amplifier remodel immunosuppressive microenvironment to boost cancer immunotherapy

• A novel tumor-permeated ATP-based size-controllable immunogenic cell death amplifier (NABP@SNCs) was fabricated for the first time to boost cancer immunotherapy. • ATP was smartly loaded and released into extracellular regions of tumor tissues through pH reversible borate ester bonds between ribose of ATP and phenylboronic acid of platinum nanoparticles (BP) for site-specific immune amplification. • NABP@SNCs could significantly amplify ICD cascade through ATP-assisted dendritic cells recruitment and eventually facilitate antitumor immune response together with NLG919 mediated TIM reversal. • This novel NABP@SNCs will provide a novel viewpoint for cancer immunotherapy and further explore the application of ATP in cancer immunotherapy. Increase extracellular adenosine triphosphate (ATP, a necessary eat me signal for ICD) is a facile way to amplify immunogenic cell death (ICD) cascade for cancer immunotherapy. However, it is still challenging for intratumoral delivery ATP due to complicated enzyme environment in the whole body. Furthermore, tumor immunosuppressive microenvironment (TIM) also hampers the function of mature DCs and limit the activation of immune response. To overcome these drawbacks, a tumor-permeated ATP-based immunogenic cell death amplifier (NABP@SNCs) is fabricated for the first time. (Phenylboronic acid-polyethylene glycol-phenylboronic acid) PBA-PEG-PBA stabilized ultrasmall platinum nanoparticles (ABP) is constructed and interacted with ATP through borate ester bond. Indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor NLG919 and ABP are co-wrapped with MMP-2 sensitive framework to form NABP@SNCs. NABP@SNCs can not only protect ATP degradation but also release small sized ABP under MMP-2 microenvironment for tumor penetration. Interestingly, ATP can also be released into extracellular regions in tumor acidic pH and act as ‘eat me signal’ for DCs maturation. Synergistically ICD activation by BP (PBA-PEG-PBA stabilized ultrasmall platinum nanoparticles) and TIM reversal by NLG919 can facilitate T lymphocyte cells infiltration for immune response. NABP@SNCs can significantly regress tumor growth and reduce pulmonary metastasis for improved cancer immunotherapy.