CD38 Protein: A Pivotal Regulator in Immunity and Metabolism, Driving a Revolution in Hematologic Malignancy Treatment

CD38 is a type II transmembrane glycoprotein with dual functions: it serves as both an important immune cell surface receptor and adhesion molecule, as well as a key extracellular enzyme (cADPR hydrolase/NAD+ glycohydrolase). Highly expressed on plasma cells, activated lymphocytes, and various cancer cells, it profoundly influences cell activation, proliferation, and survival by regulating intracellular calcium signaling and NAD+ metabolism. CD38 has become a cornerstone therapeutic target for hematological malignancies such as multiple myeloma, with related monoclonal antibody drugs revolutionizing disease treatment paradigms and showing broad potential in autoimmune diseases and other fields.

CD38 is a single-chain transmembrane glycoprotein with a molecular weight of approximately 46 kDa.
Structural features: Its intracellular and transmembrane segments are short, while its extracellular segment is long and contains a catalytic active pocket, which is key to its enzymatic function.
Expression profile:
Normal tissues: Expressed on activated T and B lymphocytes, plasma cells, natural killer cells (NK), and myeloid cells. Weak expression is also observed in hematopoietic stem cells, neurons, and renal tubular cells.
Pathological states: Abnormally high expression on various malignant hematological tumor cells, especially plasma cells (e.g., multiple myeloma) and lymphocytes.

CD38's core functions revolve around its potent extracellular enzymatic activity, primarily catalyzing two reactions:
Cyclase activity: Uses NAD+ as a substrate to generate cyclic adenosine diphosphate ribose (cADPR).
Hydrolase activity: Hydrolyzes cADPR and NAD+ to produce adenosine diphosphate ribose (ADPR) and the final metabolite adenosine.
These catalytic products collectively form a critical regulatory network:
Regulation of intracellular calcium ion concentration: cADPR is an endogenous agonist of Ryanodine receptors (RyR), triggering endoplasmic reticulum calcium release, thereby broadly influencing cell activation, proliferation, migration, and gene expression.
Depletion of key metabolite NAD+: CD38 is the major extracellular NAD+ hydrolase in mammals. By depleting NAD+ in the microenvironment, it affects cellular energy metabolism (NAD+ is a core coenzyme in redox reactions), DNA repair, and stress responses.
Generation of immunosuppressive molecule adenosine: Adenosine binds to A2A receptors on immune cells, strongly inhibiting T cell and NK cell immune functions, creating an immunosuppressive microenvironment.
Thus, CD38 is not merely a cell surface marker but a key regulator that actively shapes the local immune and metabolic microenvironment through its metabolites.

Multiple myeloma (MM):
Signature target: CD38 is uniformly, stably, and highly expressed on myeloma cells, making it an almost ideal therapeutic target.
Pathogenic role: Promotes tumor cell proliferation and survival via the cADPR/calcium signaling pathway; inhibits anti-tumor immunity by depleting NAD+ and generating adenosine, aiding tumor immune evasion.
Acute myeloid leukemia (AML): Some subtypes (particularly those with poor prognostic karyotypes) highly express CD38, correlating with disease progression and stem cell characteristics.
Acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and certain lymphomas: Also exhibit varying degrees of expression, representing potential targeted therapy directions.

Systemic lupus erythematosus (SLE):
Mechanism: Patients exhibit hyperactivated CD38-high plasma cells (secreting autoantibodies), and CD38 may contribute to immune tolerance breakdown via adenosine pathways.
Therapeutic potential: Targeting CD38 to eliminate pathogenic plasma cells has emerged as a novel strategy for SLE treatment, with clinical trials showing promise.
Rheumatoid arthritis (RA), autoimmune hemolytic anemia, etc.: Abnormally activated B cells/plasma cells may also be targets for CD38-directed therapies.

Solid tumors: Some solid tumors (e.g., prostate cancer, pancreatic cancer) may feature immunosuppressive cells in the microenvironment that highly express CD38, impacting immunotherapy efficacy.
Aging and metabolism: CD38 expression increases with age and is a key factor in declining tissue NAD+ levels, associated with age-related functional decline.

Flow cytometry immunophenotyping: CD38 is a core marker for identifying plasma cells and activated lymphocytes, used in MM, CLL diagnosis, subtyping, and minimal residual disease (MRD) monitoring.
Prognostic assessment: In CLL, CD38 positivity often indicates a more aggressive disease course.

CD38-targeted monoclonal antibodies represent one of the most successful breakthroughs in hematological oncology over the past decade, with diverse mechanisms of action (see figure):
Antibody-dependent cell-mediated cytotoxicity (ADCC): Recruits and activates NK cells via the Fc segment to kill tumor cells.
Antibody-dependent cellular phagocytosis (ADCP): Macrophages phagocytose antibody-coated tumor cells via Fc receptors.
Complement-dependent cytotoxicity (CDC): Activates the complement system to form membrane attack complexes that lyse cells.
Direct apoptosis induction: Triggers programmed cell death by crosslinking CD38 or interfering with its signaling pathways.
Immunomodulation: Clears immunosuppressive regulatory T and B cells and reduces adenosine production, reshaping the tumor microenvironment to enhance anti-tumor immunity.
Representative drugs:
Daratumumab: The first globally approved CD38-targeted monoclonal antibody, now a cornerstone of MM first-line and relapse treatment regimens, significantly prolonging patient survival.
Isatuximab: Another CD38 monoclonal antibody with a unique direct apoptosis-inducing mechanism, also approved for MM treatment.

Combining CD38 monoclonal antibodies with proteasome inhibitors, immunomodulators, chemotherapy, or novel immunotherapies shows significant synergistic effects, forming the backbone of modern MM treatment regimens.

Resistance mechanisms: Some patients develop resistance due to CD38 downregulation or effector cell exhaustion post-treatment.
Infusion reactions: Initial infusions may trigger cytokine release syndrome (CRS) and other reactions.
Infection risk: Long-term deep B cell and plasma cell depletion may increase infection risks, particularly herpes zoster virus reactivation.

Novel CD38-targeted therapies:
Bispecific antibodies: Developing bispecific antibodies targeting both CD38 and T cell CD3 to redirect T cell killing.
Antibody-drug conjugates (ADCs): Delivering cytotoxic drugs precisely to CD38-positive cells.
CAR-T/CAR-NK cell therapies: Developing CD38-targeted cell therapies for patients resistant to monoclonal antibodies.
Expanding disease areas: Further exploring CD38 monoclonal antibodies in autoimmune diseases (e.g., SLE) and plasma cell disorders like AL amyloidosis.
Overcoming resistance: Investigating resistance mechanisms and developing synergistic drugs (e.g., anti-CD47 antibodies) to reverse immunosuppressive microenvironments.
Aging intervention: Developing selective CD38 small-molecule inhibitors to elevate tissue NAD+ levels and delay age-related diseases.

CD38 has evolved from a multifunctional cell surface molecule and metabolic enzyme into a revolutionary target that has transformed the treatment paradigm for multiple myeloma, exemplifying the integration of basic research and clinical translation. By uniquely bridging immune regulation and metabolic control, it plays a central role in tumor immune evasion. Daratumumab and other CD38 monoclonal antibodies have not only brought profound benefits to hematological malignancy patients but also opened new avenues for targeting plasma cells and the metabolism-immune axis in autoimmune diseases. As understanding of its biological functions deepens and novel therapies continue to emerge, CD38-targeted strategies will play an increasingly pivotal role across a broader spectrum of diseases.