Plant Endophytic Microorganisms and Anticancer Natural Products: A Critical Reappraisal of Biosynthetic Evidence and Mechanistic Claims

Endophytic microorganisms have attracted considerable attention as a potential resource for the discovery and sustainable production of anticancer natural products. However, studies reporting the detection of target compounds from bacterial/fungal strains or elevated levels of these compounds in host plants do not constitute conclusive evidence that the microorganisms possess the capacity for independent de novo biosynthesis or are directly involved in their biosynthetic pathways. Therefore, there is a pressing need to establish an evaluation framework capable of distinguishing the genuine contribution of endophytes from false-positive signals. In this review, we systematically summarize research progress on endophytic microorganisms associated with paclitaxel, camptothecin, Catharanthus alkaloids, and podophyllotoxin as representative cases. We propose a central hypothesis that endophytes are dynamic participants in plant–microbe metabolic networks and can cooperate with their hosts to synthesize anticancer natural products through multiple mechanisms. A dual-standard evaluation system—comprising three levels of evidence and four categories of limitations—is employed to assess the quality of existing studies on microbial synthesis of plant-derived antitumor metabolites. Currently, a large number of reports remain at the level of mere in vitro culture and detection, lacking mechanistic evidence from genetic or isotopic tracing studies, which results in blurred boundaries between host residue and genuine microbial synthesis. We structurally classify endophytic contribution mechanisms into distinct types, including autonomous synthesis, host-induced synthesis, and co-metabolic conversion, and grade the quality of existing studies according to evidence strength. This dual-standard framework provides an evaluative basis for delineating the boundaries among autonomous synthesis, host induction, co-metabolic conversion, and contamination misassignment, while offering an evidence-based standard to guide the screening of anticancer endophyte resources, optimization of experimental design, and decision-making regarding microbial alternative production.