In a nutshell: Pandora's Box-B-cell lymphoproliferation masking inborn errors of immunity.

Immunodeficiency can precede and directly contribute to cancer development, particularly in B-cell lymphoproliferative disorders (B-CLPDs), where immune dysfunction is often intrinsic to the disease. A subset of such patients initially classified as having secondary immunodeficiency (SID) resulting from the BCLP may harbour underlying primary immunodeficiencies (PIDs). Recognizing the pattern of these hidden PID patients not only refines disease classification but also expands our understanding of the genetic determinants of cancer-associated immunodeficiency. Identification of tumour somatic variants that overlap with germline genes causative of PID uncovers novel mechanisms of immune dysfunction in B-CLPD, thereby providing new avenues for precision oncohaematology. This evolving host-centred perspective supports individualized, anticipatory care; enhances early detection of immune-mediated complications enabling tailored treatment responses; provides informed family counselling; and improves long-term outcomes for patients.