The paradigm of cancer treatment has been reshaped by chimeric antigen receptor (CAR) αβ T cell therapy, yet its full potential remains constrained by fundamental limitations. While conventional CAR αβ T cells have achieved notable success in hematological malignancies, their broader application is hindered by the high cost and delays of autologous manufacturing, as well as the critical risk of graft-vs-host disease (GvHD). In addition, their efficacy against solid tumors is often compromised by the immunosuppressive tumor microenvironment (TME). As a promising solution, γδ T cells are being developed as an alternative CAR platform. Their intrinsic ability to recognize transformed cells in a major histocompatibility complex (MHC)-independent manner minimizes the risk of GvHD and supports the creation of safe, effective allogeneic therapies. Building on this unique biology, the therapeutic efficacy of CAR γδ T cells is being enhanced through advanced engineering strategies. Key innovations include “armoring” technologies, such as cytokine secretion, checkpoint blockade, and metabolic rewiring, to overcome local immunosuppression and improve persistence, as well as the use of induced pluripotent stem cells (iPSCs) to generate standardized products from a renewable and consistent source. This expanding technological toolbox is also enabling novel applications beyond oncology. For example, chimeric autoantibody receptor (CAAR) constructs built on γδ T cells integrate both classical and emerging insights into CAR γδ T cell therapy, highlighting innovations that are driving the field toward safer, more versatile, and longer-lasting treatments for cancer and autoimmunity. In light of these advancements, this review provides an overview of the current understanding of γδ T cell biology and highlights emerging engineering strategies that enhance the efficacy and durability of CAR γδ T cells across oncologic and autoimmune contexts.

AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine kinase that functions as a central regulator of cellular energy status. In cancer, where metabolic reprogramming enables rapid proliferation and survival under stress, AMPK functions as a metabolic checkpoint that restrains tumor growth by inhibiting biosynthetic pathways and promoting catabolic processes, such as autophagy and fatty acid oxidation. Given its role in opposing many hallmarks of cancer metabolism, AMPK has attracted significant interest as a therapeutic target. This review examines the molecular mechanisms by which AMPK influences tumor progression and evaluates the preclinical and clinical evidence for pharmacological AMPK activation using agents such as metformin, phenformin, and canagliflozin. While promising anti-tumor effects have been reported in specific contexts—such as HER2-positive breast cancer, colorectal cancer, and metabolically distinct lung cancer subtypes—clinical efficacy remains variable. Limitations include indirect activation mechanisms, low tissue penetrance, tumor heterogeneity, and lack of reliable biomarkers for patient selection. We discuss emerging strategies to overcome these challenges, including combination therapies, metabolic stratification, and the development of direct AMPK activators or mRNA-based delivery platforms. Together, these insights support a renewed focus on AMPK as a modifiable node in cancer metabolism and a candidate for integration into precision oncology frameworks.