Leveraging intraperitoneal delivery of toll-like receptor agonists to treat peritoneal metastases.

INTRODUCTION: Peritoneal metastases (PM) remain a major clinical challenge, marked by poor prognosis and a profoundly immunosuppressive tumor microenvironment. Toll-like receptor (TLR) agonists are particularly attractive due to their ability to activate both innate and adaptive immunity, effectively converting 'cold' tumors. However, systemic administration of TLR agonists is hampered by rapid clearance and dose-limiting toxicity. Intraperitoneal (IP) delivery of TLR provides a pharmacokinetic and immunologic advantage in PM treatment by achieving sustained local drug concentrations in the peritoneal cavity while reducing systemic exposure. AREAS COVERED: We outline the expression, relevant signaling pathways, and immune effects of TLRs. The effects of IP delivery of TLR4, TLR9, and TLR 7/8 agonists observed in vitro and in preclinical models are systematically reviewed, including delivery as nanoparticles or as a prolonged delivery system. The available clinical studies are reviewed, and challenges and future directions are discussed. A systematic literature search across major databases until January 2026 supports these findings. EXPERT OPINION: Preclinical models and early clinical trials have demonstrated that intraperitoneal administration of TLR agonists can modulate the peritoneal immune microenvironment, reverse local immunosuppression, and synergize with other therapies. Together, the evidence supports IP TLR agonist therapy as a novel and promising strategy for the treatment of peritoneal metastases.