Resolving Cancer: Specialized Pro-resolving Mediators as Host-Directed Regulators of Tumor Progression and Therapy...

Cancer is sustained not only by pro-inflammatory signaling but also by inadequate restoration of tissue homeostasis, e.g., failed or dysregulated resolution. Specialized pro-resolving mediators (SPMs) are enzymatically generated lipid autacoids that actively coordinate termination of inflammation, including limiting neutrophil influx, stimulating macrophage efferocytosis, counter-regulating inflammatory mediator production, and supporting tissue repair and regeneration. In oncology, these processes intersect with tumor progression, perioperative biology, treatment-induced cell death, immunotherapy responsiveness, and late metastatic recurrence. Since 2021, major advances have reframed how we view SPMs in the context of cancer: (i) efferocytosis has emerged as a central but paradoxical mechanism that can both suppress debris-driven inflammation and enable tumor immune escape; (ii) resolution-phase macrophage mediators have been reported to target dormant disseminated tumor cells and their fibrotic niche; (iii) resolution defects linked to impaired SPM biosynthesis (including ALOX15 loss) may explain inconsistent omega-3 prevention trials; (iv) neutrophil extracellular traps (NETs) have become a rapidly expanding interface between inflammation, therapy stress, and metastatic risk; and (v) mechanistic updates, including SPM receptor signaling models, have sharpened the need for rigorous, context-aware interpretation. This chapter focuses specifically on cancer biology and translation, positioning SPMs as unique host-directed modulators with attractive potential for therapeutic intervention in cancer treatment and cancer prevention. Rather than blocking inflammation, SPMs actively reprogram inflammatory responses to maintain tumor dormancy and precancer conditions. This distinction is particularly relevant in cancer, where chronic non-resolving inflammation arises not only from tumor biology itself but also from therapeutic interventions such as surgery, chemotherapy, cytotoxic and immune-targeting therapy, and radiation.