Discovery of a Chimeric\nPolyketide Family as Cancer\nImmunogenic Chemotherapeutic Leads

Discovery of cancer immunogenic chemotherapeutics\nrepresents\nan\nemerging, highly promising direction for cancer treatment that uses\na chemical drug to achieve the efficacy of both chemotherapy and immunotherapy.\nHerein, we report a high-throughput screening platform and the subsequent\ndiscovery of a new class of cancer immunogenic chemotherapeutic leads.\nOur platform integrates informatics-based activity metabolomics for\nthe rapid identification of microbial natural products with both novel\nstructures and potent activities. Additionally, we demonstrate the\nuse of microcrystal electron diffraction (MicroED) for direct structure\nelucidation of lead compounds from partially purified mixtures. Using\nthis strategy to screen geographically and phylogenetically diverse\nmicrobial metabolites against pseudomyxoma peritonei, a rare and severe\ncancer, we discovered a new class of leads, aspercyclicins. The aspercyclicins\nfeature an unprecedented tightly packed polycyclic polyketide scaffold\nthat comprises continuous fused, bridged, and spiro rings. The biogenesis\nof aspercyclicins involves two distinct biosynthetic pathways, leading\nto formation of chimeric compounds that cannot be predicted by bottom-up\napproaches mining natural product biosynthetic genes. With comparable\npotency to some clinically used anticancer drugs, aspercyclicins are\nactive against multiple cancer cell types by inducing immunogenic\ncell death (ICD), including the release of damage-associated molecular\npatterns and subsequent phagocytosis of cancer cells. The broad-spectrum\nICD-inducing activity of aspercyclicins, combined with their low toxicity\nto normal cells, represents a new class of potential cancer immunogenic\nchemotherapeutics and, particularly, the first drug lead for pseudomyxoma\nperitonei treatment.