Combretastatin A4 Nanoparticles Combined with Hypoxia-Sensitive Imiquimod: A New Paradigm for the Modulation of Host Immunological Responses during Cancer Treatment

Vascular disrupting agents (VDAs) have great potential in cancer treatment. However, in addition to their direct tumoral vascular collapse effect, VDAs activate host immunological responses, which can remarkably impair their anticancer efficacy. Here, a VDA nanomedicine, poly­(l-glutamic acid)-graft-methoxy poly­(ethylene glycol)/combretastatin A4 (CA4-NPs), is found to induce the intratumor infiltration of immature plasmacytoid dendritic cells (pDCs), thereby curtailing anticancer immunity. To overcome this problem, hypoxia-sensitive imiquimod (hs-IMQ) is developed, which is selectively activated into imiquimod (IMQ) in treated tumors following the catalysis of CA4-NPs-induced nitroreductase (NTR). The combination of hs-IMQ and CA4-NPs causes a 6.3-fold enhancement of active IMQ concentration in tumors, as compared to hs-IMQ treatment alone. The in situ-generated IMQ alters the tumor microenvironment from a state of immunosuppression to immune activation. Hs-IMQ achieves this effect through the conversion of immature pDCs into their active form, leading to the robust infiltration and priming of natural killer cells and cytotoxic T-lymphocytes in treated tumors. Thus, the CA4-NPs and hs-IMQ combination treatment synergistically inhibits tumor growth and metastasis in 4T1 tumor-bearing mice. This work offers new approaches to harness intratumor pDCs to reverse the immune suppression resulting from VDA treatment. These findings additionally provide a mechanistic rationale for the use of VDAs in combination with TLR agonists to trigger in situ immune activation and enhance anticancer efficacy.