Potential of medicinal mushroom extracts as adjunctive agents to enhance conversion therapy in colorectal cancer with liver and peritoneal metastases

Colorectal cancer (CRC) with liver metastases (LM) and peritoneal metastases (PM) presents a formidable challenge with poor prognosis despite advances in systemic chemotherapy and combined surgical approaches, including cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Median overall survival (OS) for such unresectable cases ranges from 12 to 24 months with modern regimens (e.g., 5-fluorouracil [5-FU], leucovorin, and oxaliplatin/5-FU, leucovorin, and irinotecan + targeted therapies). However, conversion to resectable diseases remains limited by disease extent and treatment toxicity. This paper proposes that medicinal mushroom extracts, particularly polysaccharides (e.g., polysaccharide krestin and polysaccharopeptide) from Trametes versicolor and bioactive compounds from species, such as Ganoderma lucidum, could enhance conversion therapy outcomes in CRC with LM and PM. Evidence from pre-clinical and clinical studies demonstrates that these extracts exert anticancer effects through multiple mechanisms, including suppression of multidrug resistance, blockade of immune checkpoints (e.g., programmed cell death protein 1/programmed death-ligand 1), regulation of oncogenic signaling pathways (e.g., phosphoinositide 3-kinase/protein kinase B, mitogen-activated protein kinase, and Nuclear factor kappa-light-chain-enhancer of activated B cells), and robust immunomodulation. Meta-analyses of over 8,000 patients reported improved survival and tolerability when combining the extracts with chemotherapy post-surgery. Similarly, meta-analysis in the present study, involving 2,397 patients, reveals a 10% relative increase in the probability of survival at 5 years, with a survival risk ratio of 1.10 (95% confidence interval: 1.04–1.15), based on post-operative data without direct pre-operative validation. Integrating these extracts into neoadjuvant regimens could enhance chemotherapy efficacy, increase surgical eligibility, and mitigate toxicity, potentially extending OS. While direct evidence in unresectable CRC with dual metastases is lacking, the biological plausibility and safety profile of mushroom extracts warrant prospective trials to validate their role in conversion therapy.