OsteoBites welcomes Caroline Maloney, MD, PhD, from the Medical College of Wisconsin, who will discuss her research on surgery-accelerated metastasis and developing perioperative therapies.

Pulmonary metastasis remains the major cause of death in osteosarcoma. The timing of metastatic relapse defines clinically meaningful subgroups in osteosarcoma with patients who relapse within 6–12 months of surgical removal of their primary tumor having markedly worse survival (10-20%) than those who relapse after completion of therapy (40-50%). While surgical removal of the primary tumor is a fundamental component of the clinical care of solid tumors, surgery induces transient but profound changes in immune and inflammatory responses that can paradoxically accelerate the growth of metastatic disease. Dr. Maloney has demonstrated that surgical removal of the primary tumor accelerates the growth of pre-existing pulmonary metastatic disease and promotes expansion of M2‐like macrophages in the lung microenvironment. Strikingly, short term perioperative treatment with a RIPK2 inhibitor blocks this effect and reprograms macrophages toward an M1-like phenotype, implicating the NOD2–RIPK2 innate immune pathway as a key mediator of post‐surgical immune reprogramming. In contrast, the NOD2 agonist Mifamurtide has shown clinical efficacy when administered as adjuvant therapy to metastatic osteosarcoma patients after primary tumor resection. This data suggests that NOD/RIPK2 signaling may exert context-dependent effects, promoting either pro- or anti-tumor myeloid responses depending on the timing of activation relative to surgery. Understanding how surgical tumor removal alters systemic innate immunity and how RIPK2 signaling orchestrates these responses could identify new strategies to prevent early pulmonary relapse after surgery.