Intersection Between Systemic Autoimmune Diseases, Primary Immunodeficiency and Cancer: a Field in its Infancy

PURPOSE: Systemic autoimmune diseases and primary immunodeficiencies/inborn errors of immunity (PIDs/IEIs) have traditionally been viewed as opposing immunological entities. However, growing genetic, immunological, and clinical evidence challenges this dichotomy, revealing a shared spectrum of immune dysregulation, genetic vulnerability, and convergent phenotypes. Advances in next-generation sequencing have identified monogenic IEIs presenting with autoimmune manifestations indistinguishable from polygenic systemic autoimmune diseases, blurring diagnostic boundaries and carrying therapeutic implications. This review aims to explore the relationships between autoimmunity, immunodeficiency, and malignancy, emphasizing how immune dysregulation underlies susceptibility to infections, cancer, and treatment-related complications. METHODS: We performed a narrative review of the literature with a focus on underlying mechanisms, clinical manifestations, and implications for diagnosis and management. RESULTS: Immune dysregulation underlies susceptibility to infections, cancer, and treatment-related complications. Immunosuppressive and biologic/targeted therapies remain cornerstone treatments but entail risks, including serious and opportunistic infections, organ toxicity, and malignancy, particularly when underlying PIDs/IEIs remain unrecognized. Failure to recognize underlying PID/IEI in patients with early-onset, refractory, syndromic, or otherwise atypical autoimmune disease leads to misdiagnosis and harmful therapeutic escalation, underscoring the need for prompt immunological screening. Immunological screening, including immunoglobulin profiling, lymphocyte subsets, and genetic testing, may improve diagnostic accuracy and guide treatment strategies. Malignancy represents an intersection point, with disease-specific cancer patterns reflecting distinct pathogenic mechanisms across autoimmune diseases and IEIs, highlighting the clinical relevance of disease-specific cancer risk stratification and surveillance. CONCLUSION: Integrating mechanistic insights and genetic profiling may enable a precision medicine approach that optimizes efficacy while minimizing harm across this expanding immunological continuum.