# Harnessing Endophytic Fungi as a Sustainable Source of Novel Anticancer Agents: Opportunities, Challenges, and Future Directions

## TL;DR

Endophytic fungi offer a sustainable source of diverse anticancer compounds that could overcome current therapy limitations.

## Contribution

This paper reviews endophytic fungi as a novel source of anticancer agents with multi-target mechanisms and reduced toxicity.

## Key findings

- Endophytic fungi produce diverse metabolites that disrupt cancer pathways and induce apoptosis.
- Strategies like OSMAC and synthetic biology can enhance discovery and yield of bioactive compounds.
- Endophyte-derived agents show potential for scalable and eco-friendly cancer treatment.

## Abstract

Despite significant advances in oncology, current cancer therapies remain constrained by toxicity, resistance, and limited selectivity. Endophytic fungi symbiotic microorganisms inhabiting plant tissues represent a sustainable and underexplored source of structurally diverse anticancer metabolites. These include alkaloids, terpenoids, polyketides, and peptides that disrupt microtubule dynamics, interfere with DNA replication, and induce mitochondrial-mediated apoptosis. They also modulate key oncogenic signalling pathways such as nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), thereby enhancing the efficacy of existing chemotherapies. Endophyte derived compounds further inhibit angiogenesis, suppress metastasis, and stimulate immune responses, offering multi-target mechanisms with reduced toxicity. This review examines strategies that enhance the discovery and yield of these bioactive metabolites, including One Strain Many Compounds (OSMAC), microbial co-culture, epigenetic activation, genome mining, and synthetic biology. A comparative assessment of endophyte-derived versus conventional anticancer agents highlights their potential for scalable, eco-sustainable production. Collectively, endophytic fungi are positioned as promising contributors to the next generation of accessible, cost-effective, and environmentally responsible anticancer therapies.