The complement system at the crossroads of immunology, immunotherapy and hemato-oncology

The complement system, a cornerstone of innate immunity, has long been viewed through a classical lens — as a rigid cascade primarily responsible for pathogen clearance, immune complex disposal, and the orchestration of anaphylactic responses. However, a profound paradigm shift is underway. Driven by milestones in translational research, the complement system is now recognized as a highly dynamic, finely tuned regulatory network whose balance between activation and inhibition is a critical determinant of cell survival and homeostasis within the vascular compartment and the bone marrow microenvironment. Historically, hematology has served as the ultimate proving ground for complement biology: it is through the prism of hematological disorders that the intricate mechanisms of complement regulation were first decoded, and it is within this field that the most avant-garde targeted therapies continue to emerge. The most iconic manifestation of disrupted complement regulation — Paroxysmal Nocturnal Hemoglobinuria (PNH) — elegantly demonstrated how the loss of GPI-anchored protective shields renders host cells vulnerable to continuous alternative pathway tick-over and intravascular hemolysis. This Research Topic aims to capture this paradigm shift by bridging innate immunity and advanced hematology, illuminating fundamental biological mechanisms and charting the course for safer, more personalized therapeutic interventions.The primary objective of this Research Topic is to explore the complement system as both a source of pathology and a potent effector mechanism to be harnessed across the spectrum of hemato-oncological and immunological disease. Complement-dependent cytotoxicity (CDC) is a pivotal driver of the efficacy of monoclonal antibodies such as anti-CD20 (rituximab) and anti-CD38 (daratumumab), yet clinical observations have revealed that overexpression of membrane-bound complement regulatory proteins (mCRPs) on malignant cells constitutes a major immune escape mechanism, shaping the next generation of bioengineering strategies. Concurrently, the therapeutic landscape is moving beyond terminal C5 blockade: proximal inhibition targeting C3, C1s, factor D, and factor B is redefining treatment algorithms across Cold Agglutinin Disease (CAD), atypical Hemolytic Uremic Syndrome (aHUS), and transplant-associated thrombotic microangiopathies (TA-TMA). Perhaps the most exhilarating frontier lies at the intersection of complement biology and advanced cellular and gene therapies, where the complement system acts simultaneously as a barrier — challenging CAR-T cell persistence and viral vector transduction efficiency — and as a trigger, fuelling thrombo-inflammatory loops that can exacerbate cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). We aim to spotlight investigations that navigate these dynamic interactions through innovative cellular engineering, molecular armor strategies, and peri-procedural complement inhibition.This Research Topic welcomes original contributions that place complement biology at the core of their investigation into immunological, hematological, and oncological disease, across clinical, translational, and experimental domains. We welcome Original Research, Reviews, Mini Reviews, Brief Research Reports, Hypothesis and Theory, and Methods articles with a clear focus on complement mechanisms, whether through pathway analysis, biomarker discovery, therapeutic targeting, or cellular engineering. Topics of interest include, but are not limited to:o Complement regulation in the bone marrow microenvironment and vascular compartment, and its role in hematopoietic cell survival and homeostasis o Pathophysiology and therapeutic advances in PNH, with a focus on proximal complement inhibition and extravascular hemolysis o Complement-dependent cytotoxicity (CDC) as an effector mechanism of anti-CD20 and anti-CD38 monoclonal antibody therapies o mCRP overexpression as a tumor immune escape mechanism and its implications for antibody engineering and combination strategies o Proximal complement inhibitors (C1s, C3, factor D, factor B) in CAD, aHUS, and TA-TMA following allogeneic hematopoietic cell transplantation o Complement as a barrier to CAR-T cell persistence and adeno-associated virus (AAV) gene delivery vector transduction o Complement activation in cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) o Molecular armor strategies — including mCRP engineering on effector cells — and peri-procedural complement inhibition in cellular and gene therapieso Translational and clinical studies bridging complement biology, immunotherapy, and hemato-oncologyManuscripts that focus primarily on hematological or oncological outcomes without a substantive mechanistic focus on complement pathways fall outside the scope of this collection. Topic editors: Boguslaw Machalinski, Jacek M Roliński, Marcin Pasiarski Source: https://www.frontiersin.org/research-topics/85324/the-complement-system-at-the-crossroads-of-immunology-immunotherapy-and-hemato-oncology