Background: Glioblastoma (GBM) treatment is undermined by the suppressive tumor immune microenvironment (TIME). Seek for effective methods for brain TIME modulation is a pressing need. However, there are two major challenges against achieving the goal: first, to screen the effective drugs with TIME-remodeling functions and, second, to develop a brain targeting system for delivering the drugs. Methods: In this study, an α7 nicotinic acetylcholine receptors (nAChRs)-binding peptide ^DCDX was used to modify the codelivery liposomes to achieve a ‘three-birds-one-stone’ delivery strategy, that is, multi-targeting the glioma vessel endothelium, glioma cells, and tumor-associated macrophages that all overexpressed α7 nAChRs. A brain-targeted liposomal honokiol and disulfiram/copper codelivery system (CDX-LIPO) was developed for combination therapy via regulating mTOR (mammalian target of rapamycin) pathway for remodeling tumor metabolism and TIME. Honokiol can yield a synergistic effect with disulfiram/copper for anti-GBM. Results: It was demonstrated that CDX-LIPO remarkably triggered tumor cell autophagy and induced immunogenic cell death, and meanwhile, activated the tumor-infiltrating macrophage and dendritic cells, and primed T and NK (natural killer) cells, resulting in antitumor immunity and tumor regression. Moreover, CDX-LIPO promoted M1-macrophage polarization and facilitated mTOR-mediated reprogramming of glucose metabolism in glioma. Conclusion: This study developed a potential combinatory therapeutic strategy by regulation of TIME and a ‘three-birds-one-stone’-like glioma-targeting drug delivery system.

Background: There are few effective medications for treating colorectal cancer and liver metastases (CRLM). The interactions among glycolysis, epithelial-mesenchymal transition (EMT), and immune microenvironment contribute to the progression of CRLM. A main glycolytic enzyme pyruvate Kinase M2 (PKM2) is highly expressed in colorectal cancer and CRLM, and thus can be a potential therapeutic target. Methods: A therapeutic strategy was proposed and the shikonin-loaded and hyaluronic acid-modified MPDA nanoparticles (SHK@HA-MPDA) were designed for CRLM therapy via PKM2 inhibition for immunometabolic reprogramming. The treatment efficacy was evaluated in various murine models with liver metastasis of colorectal tumor. Results: SHK@HA-MPDA achieved tumor-targeted delivery via hyaluronic acid-mediated binding with the tumor-associated CD44, and efficiently arrested colorectal tumor growth. The inhibition of PKM2 by SHK@HA-MPDA led to the remodeling of the tumor immune microenvironment and reversing EMT by lactate abatement and the suppression of TGFβ signaling; the amount of cytotoxic effector CD8⁺ T cells was increased while the immunosuppressive MDSCs decreased. Conclusion: The work provided a promising targeted delivery strategy for CRLM treatment by regulating glycolysis, EMT, and anticancer immunity. Graphic An immunometabolic strategy for treating colorectal cancer liver metastases using the shikonin-loaded, hyaluronic acid-modified mesoporous polydopamine nanoparticles (SHK@HA-MPDA) via glycolysis inhibition, anticancer immunity activation, and EMT reversal. SHK@HA-MPDA can inhibit cytoplasmic PKM2 and glycolysis of the tumor and reduce lactate flux, and then activate the DCs and remodel the tumor immune microenvironment. The reduced lactate flux can reduce MDSC migration and suppress EMT.

Background: Immunotherapy has profoundly changed the landscape of cancer management and represented the most significant breakthrough. Yet, it is a formidable challenge that the majority of cancers - the so-called “cold” tumors - poorly respond to immunotherapy. To find a general immunoregulatory modality that can be applied to a broad spectrum of cancers is an urgent need.