Strategies to Modulate Mast Cell Activation for Cancer Immunotherapy

Mast cells (MCs) are an emerging target in cancer immunotherapy due to their phenotypic plasticity, immunomodulatory capacity, and active recruitment into the tumor microenvironment (TME). While MCs can adopt both pro- and anti-tumor phenotypes, recent evidence suggests that tumors exploit this plasticity by recruiting immature MC progenitors and conditioning them toward tumor-supportive functions. Therapeutic strategies aimed at reprogramming MCs into anti-tumor effectors—rather than depleting them—are gaining traction. However, many of the most promising modulatory agents, including cationic peptides and small-molecule agonists, face significant delivery barriers due to poor systemic stability, off-target effects, and limited tumor penetration. Drug delivery systems (DDSs), particularly nanomedicine platforms, offer a powerful solution by enabling targeted, controlled, and localized delivery of these agents to MCs within the TME. In this review, we highlight the rationale for MC-targeted immunotherapy, evaluate current strategies for phenotypic modulation, and emphasize the critical role of DDSs in overcoming translational barriers. By integrating MC biology with advanced delivery technologies, we outline a path forward for harnessing this underexplored immune population in cancer treatment.