Small-molecule immunomodulators have become important components of modern immunotherapy by targeting immune checkpoints, cytokine signaling pathways, metabolic enzymes, and intracellular kinases. Despite pharmacological rationale, many of these agents underperform clinically due to unfavorable physicochemical properties, rapid systemic clearance, limited target accumulation, and dose-limiting toxicities, reflecting inadequate exposure control rather than a lack of target validity. Polymeric micelles, formed through the self-assembly of amphiphilic block copolymers, offer a versatile delivery platform to address these challenges by enhancing solubility, modulating pharmacokinetics, enabling stimuli-responsive release, and facilitating targeted or synchronized co-delivery. In this review, we classify representative small-molecule immunomodulators according to their immunological targets and examine the delivery constraints that shape their therapeutic performance. We then discuss design principles of polymeric micelle systems, including solubilization-driven formulations, microenvironment-responsive architectures, spatial targeting strategies, and co-delivery approaches that align cytotoxic and immunomodulatory mechanisms. Attention is given to the distinction between direct immunomodulators and cytotoxic agents that induce immunogenic cell death, highlighting how micelle-based delivery can enhance efficacy through improved exposure control. By integrating immunopharmacology with formulation science, this review outlines how polymeric micelles may advance the efficacy and safety of small-molecule immunomodulators and identifies key considerations for future translational development.
Suwal et al. (Sun,) studied this question.