Immunosuppressive cells residing in the tumor microenvironment, especially tumor associated macrophages (TAMs), hinder the infiltration and activation of T cells, limiting the anti-cancer outcomes of immune checkpoint blockade. Here, we report a biocompatible alginate-based hydrogel loaded with Pexidartinib (PLX)-encapsulated nanoparticles that gradually release PLX at the tumor site to block colony-stimulating factor 1 receptors (CSF1R) for depleting TAMs. The controlled TAM depletion creates a favorable milieu for facilitating local and systemic delivery of anti-programmed cell death protein 1 (aPD-1) antibody-conjugated platelets to inhibit post-surgery tumor recurrence. The tumor immunosuppressive microenvironment is also reprogrammed by TAM elimination, further promoting the infiltration of T cells into tumor tissues. Moreover, the inflammatory environment after surgery could trigger the activation of platelets to facilitate the release of aPD-1 accompanied with platelet-derived microparticles binding to PD-1 receptors for re-activating T cells. All these results collectively indicate that the immunotherapeutic efficacy against tumor recurrence of both local and systemic administration of aPD-1 antibody-conjugated platelets could be strengthened by local depletion of TAMs through the hydrogel reservoir.

Immunotherapy is leading a paradigm shift in the treatment of various diseases, including tumors, auto‐immune diseases, and infectious diseases. However, the limited response rate and systemic side effects significantly impede the clinical applications of immunotherapy. As natural carriers for proteins and molecules, cells with low immunogenicity and toxicity have attracted considerable attention for biomedical applications and have achieved encouraging progress especially in immunotherapy. The convergence of multiple disciplines has equipped cell‐based delivery systems with control over their spatiotemporal distribution to enhance treatment efficacy and reduce side effects. Here, an overview of the fundamentals and design principles of cell‐based delivery systems followed by a perspective that includes the most recent advances of various cells as delivery carriers, with a special focus on the implications of cell‐based delivery systems for immunotherapy is offered.

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