Harnessing Mn²⁺ Ions and Antitumor Peptides: A Robust Hydrogel for Enhanced Tumor Immunotherapy

Immunotherapy has attracted widespread attention because of its durable and effective antitumor properties. However, systemic delivery strategies often result in immune-related off-target toxicity effects and inadequate drug retention at the tumor site, which limits its broader application. In this research, we designed a dual-functional antitumor peptide (N-Pep) that serves as both a therapeutic agent and metal ions (Mn²⁺) immunomodulator carrier. The rational designed antitumor peptide self-assembles into a hydrogel through coordination with Mn²⁺ ions (referred to as N-Pep-Mn gel). The multiporous hydrogel network allows for efficient loading of antiprogrammed death-1 antibody (αPD-1). The hydrogel served as a depot for the sustained release of Mn²⁺ ions and encapsulated αPD-1, effectively activating dendritic cells, polarizing tumor-associated macrophages and enhancing effector T cell infiltration, thereby leading to the effective inhibition of tumor growth through intratumoral and systemic immune responses. Additionally, the hydrogel induces robust immune memory, providing substantial protection against tumor recurrence. These findings underscore the potential of Mn²⁺ ion-coordinated antitumor peptide hydrogel as an advanced platform for enhancing antitumor immunotherapy.