Efficiently restoring the tumoricidal immunity against resistant malignancies via an immune nanomodulator

Abstract

Bioinformatically triple negative breast cancer (TNBC) and colon adenocarcinoma (COAD), two typical “cold” cancers, were found overexpressed PD-L1 and CD47 respectively but neither of them showed satisfied response on its corresponding immune checkpoint blockade (ICB) in clinic. The initial immunotherapeutic resistance to ICB was essentially attributed to the so-called “cold” tumor immune milieu (TIM). To overcome tumor immunological tolerance against ICBs, here we report a versatile nano-modulator for point-to-point counteracting the immune-suppressors meanwhile boosting tumor T cell infiltration. Small interfering RNA targeting indoleamine 2,3-dioxygenase-1 was first co-delivered with gemcitabine using our lab-made biocompatible nanocages for relieving the immune brakes related to regulatory T cells and myeloid-derived suppressor cells. O2-producible mineralization was then tattooed on the surface of the nanocarriers to alleviate the immune inhibition of M2 macrophages. Followed with the decoration of therapeutic ICB antibodies on the mineralized shell, a versatile nano-modulator was constructed. TNBC and COAD were employed to evaluate the tumoricidal efficacy of the nano-modulator that decorated with aPD-L1 and aCD47, respectively. Our nano-modulator demonstrated multipotencies in eliciting a “hot” TIM and greatly potentiated ICB treatment for these “cold” malignancies. The strung expansibility of the nano-modulator may be also conducive in addressing the failure of more other ICBs on the non-responsive subpopulation of patients despite the corresponding immune checkpoint highly expressed in tumors.