GZMA/GZMB

Overview

GZMA/GZMB refers to the granzyme A and granzyme B proteins, two closely related serine proteases expressed primarily by cytotoxic lymphocytes, including CD8+ T cells, natural killer (NK) cells, and some innate-like lymphocyte populations. They are key effector molecules in cell-mediated immunity and are widely used as markers of cytotoxic immune activation. In the context of antitumor immunity, GZMA and GZMB are associated with the killing capacity of T-lymphocytes and NK cells, and their expression often reflects an active immune microenvironment.

Granzyme B, in particular, is frequently used as a functional readout of cytotoxic T-cell activity and has become a biomarker in immunotherapy research. Beyond its canonical role in inducing target-cell death, recent studies have also explored granzyme B as a measurable enzymatic target for imaging, immune monitoring, and engineered cell therapies. GZMA/GZMB are therefore relevant both as immune effectors and as translational biomarkers in cancer, inflammatory disease, and immune profiling.

Focus of Latest Publications

Recent publications have used GZMA/GZMB mainly as indicators of cytotoxic immune activation and as mechanistic mediators of antitumor responses. In a study of a bispecific macrophage nano-engager that combined dual checkpoint blockade with STING1 activation, treatment increased granzyme B, perforin, and IFN-γ production, leading to robust T-cell-dependent tumor cell killing. This places granzyme B downstream of coordinated innate and adaptive immune stimulation, with the tumor microenvironment being remodeled toward stronger effector function.

Granzyme B was also used as the basis for a CAR-T engineering strategy. One study generated granzyme B-based CAR-T cells targeting membrane-bound HSP70 to suppress solid tumor growth and metastasis. Here, granzyme B served as a natural ligand scaffold for redirecting T-cell specificity, illustrating a therapeutic design that links cytotoxic effector biology with antigen targeting in solid tumors.

In hepatocellular carcinoma research, a postbiotic from Lactobacillus kefiranofaciens ZW18 was reported to decrease FoxP3 transcript levels and increase GzmB expression in the spleen. This suggested reduced immunosuppressive Treg activity and enhanced immune activation in tumor-bearing mice. The finding connects GZMB with systemic antitumor immune reprogramming and supports its use as a marker of restored cytotoxic immunity.

Several studies used GZMB as a biomarker in immune phenotyping and disease signature development. A machine-learning analysis of abdominal aortic aneurysm identified a four-gene diagnostic signature including CXCR4, GZMB, ITGA6, and CD47, indicating that GZMB can appear in inflammatory or immune-associated transcriptional signatures beyond oncology. Another study of human T lymphocyte aging found that CD8+ T cells showed elevated cytotoxic effector molecules, including IFN-γ and granzyme B, consistent with age-associated remodeling of cytotoxic function.

Granzyme B also appeared in studies of extracellular vesicle biology and nuclear delivery. Activated T cell extracellular vesicles were shown to package granzyme B, which disrupted the nuclear envelope of recipient cells and facilitated intranuclear transfer of extracellular vesicle DNA, enabling transient expression of encoded genes. A related Cancer Cell study described T cell extracellular vesicles going nuclear to turn cold tumors hot via granzyme B-mediated nuclear delivery, linking GZMB to a novel mechanism of immune-cell communication and antitumor activation.

In imaging and assay development, granzyme B was treated as a dynamic biomarker of immune response. A near-infrared photoactivatable cascade DNAzyme nanomachine was designed for concurrent imaging of granzyme B and cathepsin B activity during STING-activated immunotherapy. Another study developed renal-clearable bio-orthogonal near-infrared fluorogenic probes to detect granzyme B for dynamic evaluation of renal cell carcinoma immunotherapy, including optical urinalysis of GzmB. These approaches underscore the value of GZMB as a noninvasive readout of cytotoxic T-cell activation in clinical and preclinical settings.

Additional studies linked GZMA/GZMB to broader immune remodeling. A supramolecular net-suppressor for renal cancer therapy increased IFN-γ and granzyme B secretion while reducing immunosuppressive Tie2-expressing monocytes, suggesting improved vascular-immune microenvironment remodeling. In a dual-targeted vaccine study against neoantigens and shared MICB α3 antigen, ILC1s with high GZMA/GZMB expression were identified as the primary tumor-infiltrating subset responsible for enhancing antitumor immunity and inducing Gasdermin D cleavage in tumor cells to initiate pyroptosis. Together, these studies position GZMA/GZMB as central effectors and biomarkers in tumor immunity, immune-cell engineering, and response monitoring.

Key Publications

• Jun Bispecific Macrophage Nano-Engager Couples Dual Checkpoint Blockade with Stimulator of Interferon Genes Activation to Potentiate Antitumor Immunity. (ACS nano, 2026, PMID 42165513): "additionally, it elevated granzyme B, perforin, and IFN-γ production, resulting in robust T-cell-dependent tumor cell killing."
• Jun Granzyme B-based CAR-T cells targeting membrane-bound HSP70 suppress solid tumor growth and metastasis. (Oncogene, 2026, PMID 42000923): "Here, we generated CAR T cells based on natural ligand granzyme B (GrB-CAR T) targeting mHSP70."
• Jun Therapeutic potential of Lactobacillus kefiranofaciens ZW18 postbiotic in alleviating hepatocellular carcinoma. (Food research international (Ottawa, Ont.), 2026, PMID 41895984): "Additionally, Post18 decreased the relative transcript levels of FoxP3 and increased those of GzmB in the spleen, suggesting that Post18 reduced the number or function of immunosuppressive Tregs and activated immune responses in HCC mice."
• May Machine learning identifies a NETs-related four-gene diagnostic signature for abdominal aortic aneurysm. (Medicine, 2026, PMID 42175497): "A robust 4-gene diagnostic signature comprising CXCR4, GZMB, ITGA6, and CD47 was identified."
• May T cell extracellular vesicles go nuclear to turn cold tumors hot. (Cancer cell, 2026, PMID 42066760): "...via granzyme B-mediated nuclear delivery, boosting antitumor immunity."
• May Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity. (Cancer cell, 2026, PMID 42066762): "Mechanistically, granzyme B (Gzmb) packaged by ATEVs disrupts the nuclear envelope of recipient cells, facilitating intranuclear transfer and subsequent transient expression of EVDNA encoding APP genes."
• May The iterative shrinkage thresholding algorithm reveals dynamic aging trajectories of human T lymphocytes via multidimensional spectral flow cytometry analysis. (International immunopharmacology, 2026, PMID 41833104): "CD8+ T cells exhibited the greatest sensitivity to age-associated immunophenotypic remodeling, characterized by elevated cytotoxic effector molecules including IFN-γ and granzyme B."
• May Evaluation of cross-reactivity of monoclonal antibodies against cytokines and cellular molecules of bovine and human origin to identify immunological markers in buffaloes (Bubalus bubalis). (Veterinary immunology and immunopathology, 2026, PMID 41864098): "sixteen commercial mAbs anti-cell markers (CD4, CD8, CD14, CD21, CD25, CD28, CD45RB, CD45RO, WC1, and CD80) and anti-cytokines or other effector molecules of the immune system (TNF-α, IFN-γ, IL-4, IL-17A, granzyme B and perforin) that recognize molecules from bovine and human species were evaluated in whole blood samples from buffaloes and cattle."
• Apr Supramolecular net-suppressor drives tumor vascular-immune microenvironment remodeling with spatiotemporal synchronization for renal cancer therapy. (Materials horizons, 2026, PMID 41705472): "RING1 enhanced vascular normalization by 1.8-fold, which subsequently reduced the population of immunosuppressive Tie2-expressing monocytes (TEMs) and elevated the secretion of IFN-γ and granzyme B."
• Apr Photoactivatable Cascade DNAzyme Nanomachines for Amplified Imaging of Tumor Response to STING-Activated Immunotherapy. (Analytical chemistry, 2026, PMID 41980121): "Herein, we report a near-infrared (NIR) photoactivatable cascade DNAzyme nanomachine (PCDzNM) designed for the concurrent, amplified imaging of granzyme B (Gzm B) and cathepsin B (Cat B) activity during STING-activated immunotherapy."