Engineering Cytokine Signaling for Precision Cancer Immunotherapy

Cytokines are central regulators of antitumor immunity, controlling the activation, differentiation, trafficking, persistence, and effector functions of immune cells. Several cytokines have demonstrated therapeutic potential in cancer, but their clinical use is often limited by short systemic half-lives, pleiotropic activity, dose-limiting toxicity, and an inability to selectively stimulate the desired immune-cell populations within tumors. Advances in protein engineering, structural immunology, synthetic biology, targeted delivery, and cell engineering are creating new opportunities to reshape cytokine activity with greater spatial, temporal, and cellular precision. Emerging approaches include affinity-tuned cytokines, receptor-biased agonists, cytokine–antibody fusion proteins, conditionally activated cytokines, tumor-targeted cytokines, orthogonal cytokine–receptor systems, and engineered immune cells with programmable cytokine circuits. These technologies may enhance antitumor efficacy while reducing systemic toxicity and overcoming immune suppression or therapeutic resistance.

This Collection will highlight mechanistic and translational advances in engineering cytokine signaling for cancer immunotherapy. We welcome original research articles, reviews, perspectives, and commentaries that examine cytokine biology in the tumor microenvironment; the design of engineered cytokines, receptors, or delivery platforms; integration of cytokine signaling with adoptive cell therapy, therapeutic antibodies, vaccines, and immune checkpoint blockade; and biomarkers or preclinical and clinical strategies that improve therapeutic selectivity, durability, and safety.

Topics of interest include, but are not limited to:

• Cytokine signaling mechanisms in antitumor immunity and the tumor microenvironment

• Protein engineering of cytokines and cytokine receptors

• Affinity-tuned, receptor-biased, or cell-selective cytokine agonists

• Tumor-targeted cytokines and cytokine–antibody fusion proteins

• Conditionally activated, masked, or protease-responsive cytokine therapeutics

• Orthogonal and synthetic cytokine–receptor systems

• Cytokine circuits in CAR-T, TCR-T, NK-cell, and other adoptive cell therapies

• Local cytokine delivery using biomaterials, nanoparticles, viral vectors, or gene therapy

• Cytokine combinations with checkpoint blockade, therapeutic antibodies, or cancer vaccines

• Strategies to reduce cytokine-associated systemic toxicity and immune-related adverse events

• Cytokine-mediated resistance, immune suppression, and tumor immune escape

• Biomarkers and systems-level analyses of cytokine responses in cancer immunotherapy

• Preclinical and clinical translation of next-generation cytokine therapeutics