Scheme 1.

Hydrogels can localize the effects of CD40 agonists to reap their anti‐tumor benefits while abating their immune‐related adverse effects. A) CD40 agonist antibodies engage CD40 receptors on antigen presenting cells to potently upregulate antigen presentation, co‐stimulatory receptor expression, and secretion of immunostimulatory cytokines. Altogether, these effects potentiate T cell priming and create a more supportive environment for effector T cell function. B) Injectable, supramolecular polymer‐nanoparticle (PNP) hydrogels composed of dodecyl‐modified hydroxypropyl methylcellulose and poly(ethylene glycol)‐b‐poly(lactic acid) nanoparticles can be used to encapsulate CD40 agonists for local drug delivery. C) Peritumoral hydrogel administration leads to slow release of CD40 agonists into the local microenvironment, focusing the immunostimulatory effects on the tumor and draining lymphatics. In contrast, traditional systemic approaches lead to widespread exposure throughout the body and the occurrence of immune‐related adverse effects.