Interleukin-10 (IL-10) is an anti-inflammatory cytokine essential for immune homeostasis and the resolution of inflammation. It is produced by a diverse array of immune cells, including monocytes, macrophages, dendritic cells, regulatory T cells (Tregs), Th2 cells, B cells, and certain subsets of CD8⁺ T cells and NK cells. Through both autocrine and paracrine mechanisms, it suppresses pro-inflammatory cytokine production (e.g. TNF-α, IL-1β, IL-6) by monocytes and macrophages and promotes regulatory immune responses (Steen-Louws et al., 2019, Saraiva et al., 2020, Ouyang and O’Garra, 2019). IL-10 also influences lymphocytes, for instance enhancing survival and IFN-γ production of activated CD8+ T cells (an effect that can bolster anti-tumor immunity) (Saxton et al., 2021, Guo et al., 2021, Garcia-Lacarte et al., 2025). This pleiotropy, simultaneously dampening innate inflammation while modulating adaptive immunity, makes IL-10 a compelling but complex therapeutic agent (Fig. 1). Recombinant human IL-10 protein showed promise in early clinical trials for inflammatory diseases (e.g. psoriasis and Crohn’s disease) by reducing disease activity (Duncan et al., 2019). However, IL-10 short plasma half-life (measured in hours) necessitated frequent high dosing, and its broad activity led to context-dependent effects (including paradoxical stimulation of IFN-γ) that could counteract its benefits (Saxton et al., 2021, Duncan et al., 2019). These challenges limited the success of unmodified IL-10 therapy in chronic diseases (Duncan et al., 2019).

To harness IL-10 potent immunoregulatory functions while overcoming these limitations, researchers have pursued numerous engineering and delivery strategies. Broadly, these include: protein engineering of IL-10 variants to enhance stability or bias its signaling; fusion proteins that extend IL-10 half-life or combine it with other biomolecules for synergistic or targeted effects; encapsulation systems (nanoparticles, hydrogels, etc.) that protect IL-10 from rapid clearance and enable controlled release; targeted delivery approaches using antibodies or tissue-specific carriers to direct IL-10 to desired sites; and receptor fusion proteins (immunoadhesins) designed to modulate IL-10 pathway (for example, soluble IL-10 receptors to neutralize IL-10 in certain contexts). In the sections below, we discuss each strategy in detail, highlighting representative preclinical findings (pharmacodynamics/pharmacokinetics and efficacy in disease models) as well as any clinical-stage developments. We also critically evaluate the advantages and drawbacks of each approach, such as improved half-life, reduced off-target effects, immunogenicity risks, manufacturing feasibility, and translational readiness, in the context of various diseases such as cancer, autoimmunity, inflammatory bowel disease, fibrosis, or transplantation.