MYD88 is a critical adapter protein that mediates innate immune signaling downstream of Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs) 1. Upon activation, MYD88 recruits IRAK and TRAF6 proteins to initiate signaling cascades leading to NF-κB activation and production of inflammatory cytokines including IL-1β and IL-8, contributing to host defense against pathogens 1. MYD88 is essential for protective immunity against pyogenic bacteria; however, humans with complete MYD88 deficiency show selective susceptibility to specific bacterial pathogens while maintaining normal resistance to most other microbes, indicating functional redundancy in many immune contexts 2. Clinically, MYD88 mutations are highly relevant to hematologic malignancies. The L265P mutation in MYD88 is detected in >90% of Waldenström macroglobulinemia (WM) patients and drives disease pathogenesis by activating BTK signaling 3, 4. MYD88 mutation status serves as a prognostic marker: mutated MYD88 with wild-type CXCR4 predicts better response to Bruton tyrosine kinase inhibitors, informing treatment selection 5. The MYD88 L265P mutation also represents a diagnostic biomarker for primary CNS lymphoma, detectable in blood and cerebrospinal fluid with high sensitivity and specificity 6. Autosomal recessive MYD88 deficiency causes immunodeficiency 68, characterized by recurrent pyogenic infections.