The paradox of potency: Insights into emergent mechanisms of Ganoderma lucidum's antitumor effects

An arms race between cancer cells and therapeutic pressure fuels drug resistance, immune evasion, and tumor heterogeneity, hindering therapy. Ganoderma lucidum (G. lucidum), a traditional Chinese medicine (TCM) with multitarget pharmacology, offers potential to address this complexity. However, the mechanistic basis of the emergent effects of its meroterpenoids remains unexplored.

This study used G. lucidum meroterpenoids as a model to elucidate the mechanisms underlying emergent effects in TCM and to evaluate their therapeutic potential for overcoming tumor resistance and heterogeneity.

This study employed an integrative design combining phenotypic screening, in vitro cell-based assays, in vivo tumor xenograft models, and multiomics analyses to investigate the emergent antitumor mechanisms of G. lucidum meroterpenoids.

Meroterpenoid and polysaccharide extracts were evaluated in vitro and in vivo for their effects on TNBC growth. Transcriptomic, metabolomic, and microbiome analyses were performed to explore systemic mechanisms. Phenotypic screening and transcriptome analyses were performed to characterize the synergistic (0 + 0 + 0…>0) and potentiation (0 + 0 + 0…+1 > 1) effects of the meroterpenoid combinations and to elucidate the underlying molecular mechanisms.

In MDA-MB-231 cells, the meroterpenoid extracts inhibited proliferation and migration by inducing ferroptosis and reprogramming inflammatory signaling. In a mouse tumor model, total meroterpenoid extracts suppressed tumor growth, enriched beneficial gut microbiota, and partially restored tumor-depleted serum lipids and amino acids. Cotreatment with G. lucidum polysaccharides accelerated the restoration of the microbiota and achieved more extensive metabolomic correction. Notably, a set of inert meroterpenoids, defined as those lacking phenotypic effects, exhibited emergent anticancer activity when combined with one another or with active compounds. These combinations acted through 0 + 0 + 0…>0 synergy or 0 + 0 + 0…+1 > 1 potentiation to inhibit proliferation and migration by overcoming drug resistance, reprogramming metabolism, and inducing ferroptosis. They also triggered cell cycle collapse and necroptosis.

This case study provides insights into how meroterpenoids, particularly combinations of inert meroterpenoids, drive the emergent pharmacological effects of G. lucidum and suggests a strategy to overcome drug resistance and tumor heterogeneity.