IL-10's contextual role in cytotoxic antitumor immunity: evidence, controversies, and therapeutic translation.

Interleukin-10 (IL-10) is classically defined as a potent anti-inflammatory cytokine that protects tissues by constraining myeloid activation and limiting inflammatory cytokine production. Yet, accumulating evidence indicates that, in defined contexts, IL-10 can also promote antitumor immunity by enhancing the fitness and cytotoxic programs of CD8+ T cells and natural killer (NK) cells. Conversely, in other tumor contexts, IL-10 may reinforce immunosuppressive myeloid and regulatory programs, and the factors that determine these divergent outcomes remain incompletely understood. Although these effects converge on a common JAK1/TYK2-STAT3 signaling hub, the downstream biological outcomes are combinatorially shaped by the identity, activation, and chromatin state of the responding cell, co-engaged pathways, including STAT1, mTORC1, and NF-κB/AP, receptor abundance, feedback regulation, and the surrounding microenvironment. Recent studies suggest IL-10 can sustain cytotoxic lymphocyte function under tumor microenvironmental stress through effector programming, restraint of terminal exhaustion, mitochondrial metabolic reprogramming, and remodeling of the tumor microenvironment (TME). However, several of these mechanisms remain supported primarily by limited preclinical models and correlative human data. These advances have promoted the development of pharmacokinetically optimized IL-10 variants, tumor-targeted immunocytokines, surrogate bispecific IL-10 receptor agonists, and IL-10-armored adoptive cell therapies. Although several approaches have shown immune activation and preliminary antitumor activity in early-phase studies, pegilodecakin-the only IL-10-based agent to complete a randomized phase III oncology trial-did not improve survival in gemcitabine-refractory pancreatic cancer, underscoring the gap between pharmacodynamic activity and established clinical benefit. In this review, we synthesize mechanistic and translational advances with conflicting and cautionary evidence, discuss safety considerations associated with IL-10-based agents and IL-10-armored cell therapies, and propose a context-dependent framework for their further development based on tumor and microenvironmental features, spatiotemporal control, rational combination strategies, and candidate biomarkers.