The Granzyme (Gzm) family has classically been recognized as a cytotoxic tool utilized by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells to illicit cell death to infected and cancerous cells. Their importance is established based on evidence showing that deficiencies in these cell death executors result in defective immune responses. Recent findings have shown the importance of Granzyme B (GzmB) in regulatory immune cells, which may contribute to tumor growth and immune evasion during cancer development. Other studies have shown that members of the Gzm family are important for biological processes such as extracellular matrix remodeling, angiogenesis and organized vascular degradation. With this growing body of evidence, it is becoming more important to understand the broader function of Gzm’s rather than a specific executor of cell death, and we should be aware of the many alternative roles that Gzm’s play in physiological and pathological conditions. Therefore, we review the classical as well as novel non-canonical functions of GzmB and discuss approaches to utilize these new findings to address current gaps in our understanding of the immune system and tissue development.

The pivotal role of Granzyme B (GzmB) in immune responses, initially tied to cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, has extended across diverse cell types and disease models. A number of studies have challenged conventional notions, revealing GzmB activity beyond apoptosis, impacting autoimmune diseases, inflammatory disorders, cancer, and neurotoxicity. Notably, the diverse functions of GzmB unfold through Perforin-dependent and Perforin-independent mechanisms, offering clinical implications and therapeutic insights. This review underscores the multifaceted roles of GzmB, spanning immunological and pathological contexts, which call for further investigations to pave the way for innovative targeted therapies.

Communication between the nervous and immune systems is required for the body to regulate physiological homeostasis. Beta-adrenergic receptors expressed on immune cells mediate the modulation of immune response by neural activity. Activation of beta-adrenergic signaling results in suppression of antitumor immune response and limits the efficacy of cancer immunotherapy. Beta-adrenergic signaling is also involved in regulation of hematopoietic reconstitution, which is critical to the graft-versus-tumor (GVT) effect and to graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT). In this review, the function of beta-adrenergic signaling in mediating tumor immunosuppression will be highlighted. We will also discuss the implication of targeting beta-adrenergic signaling to improve the efficacy of cancer immunotherapy including the GVT effect, and to diminish the adverse effects including GVHD.

Beta-adrenergic receptor signaling regulates cellular processes associated with facilitating tumor cell proliferation and dampening anti-tumor immune response. These cellular processes may lead to compromised tumor control and cancer progression. Based on this ramification, Beta-blockers (BBs) have emerged as a potential treatment by inhibiting beta-adrenergic receptor signaling. This review aimed to investigate the relationship between the use of BBs and tumor progression and treatment response. Therefore, the authors explored several aspects: the potential synergistic relationship of BBs with chemotherapy and immunotherapy in enhancing the effectiveness of chemotherapeutic and immunotherapeutic treatments and their role in boosting endogenous immunity. Further, this review explores the distinctions between the major types of BBs: Non-selective Beta Blockers (NSBBs) and Selective Beta Blockers (SBBs), and their contributions to combinatory cancer treatment. In this review, we presented a perspective interpretation of research findings and future directions. Overall, this review discusses the potential and challenge that BBs present in improving the effectiveness and outcome of cancer treatment.