Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy

Abstract

Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream β-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells’ P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy.

Histone demethylase JMJD1A in cancer progression and therapeutic resistance

“…24 On the other hand, JMJD1A-mediated regulation of β-catenin can upregulate the expression of P-glycoproteins and programmed cell death-ligand 1, thereby conferring multidrug resistance and T-cell dysfunction/ exhaustion in colon cancer. 26 Thus, targeting JMJD1A can significantly enhance doxorubicin-induced immune-stimulatory immunogenic cell death. Moreover, JMJD1A can upregulate the expression of YAP1, which is a coactivator for transcription factor TEAD, through H3K9 demethylation of YAP1 gene promoter; JMJD1A also promote the recruitment of TEAD1 to the hippo target genes.…”

Advanced and Innovative Nano-Systems for Anticancer Targeted Drug Delivery

“…IOX1 (5-carboxy-8-hydroxyquinoline), a kind of histone demethylase inhibitor, is used as an antibody-free small molecular drug for immunotherapy. Liu et al fabricated IOXL by loading IOX1 into liposome with a similar formula of commercially available PEGylated liposomal DOX (PLD, LIBOD ® ) [ 9 ]. Subsequently, the mixed liposome IPLD was obtained by mixing IOXL with commercial PLD at an optimized molar ratio.…”

“…Table 1 is a summary of all th nanostructures discussed below and their corresponding encapsulation of antican agents. Promote T cell infiltration and activity, reduce tumor immunosuppressive factors, elicit long-term antitumor immunological memory, decrease the tumor growth of 4T1 orthotopic and lung metastatic dual tumors, prolong the survival for over 80 days [9] Indocyanine green Dendritic lipopeptide-mediated active targeting…”

Inhibition of post-surgery tumour recurrence via a sprayable chemo-immunotherapy gel releasing PD-L1 antibody and platelet-derived small EVs

“…We loaded DOX in Pex with the aim of neutralizing tumour cells through the specific adhesion interaction between Pex and CTCs, thereby inhibiting tumour metastasis. Pex are also smaller than platelets and can deliver drugs more effectively [ 15 , 21 , 22 ].…”