Tumor microenvironment activatable immunomodulator for cancer immunotherapy.

The tumor microenvironment (TME) represents a sophisticated ecosystem wherein resident biomaterials orchestrate therapeutic resistance, and immune evasion, making it a critical target for cancer immunotherapy. This review underscores the central role of the TME in immunomodulation and the potential of TME-activatable immunomodulators to revolutionize cancer immunotherapy. We first provide an overview of the characteristics and components within the TME that drive tumor growth and metastasis, including immune cells, stromal cells, and metabolic factors. Next, we summarize the design principles and responsive mechanisms of TME-activatable immunomodulators, covering pH, glutathione, hydrogen peroxide, enzymes, and hypoxia to enhance tumor penetration and reduce off-target effects. Preclinical successes of emerging technologies, such as immune checkpoint inhibitors, chimeric antigen receptors, mRNA vaccines, stimulator of interferon genes agonists, and proteolysis-targeting chimeras, highlight the importance of spatiotemporally controllable immunomodulator delivery leveraging these pathophysiological signals. Finally, we discuss current limitations, including TME-induced resistance mechanisms and biosafety considerations, and outline future directions for TME-activatable immunomodulators. Integrated stimuli-responsive characteristics have proven to be effective in precisely controlling the delivery and activation of immunomodulators within the complex microenvironment.