Decoding and rewiring lymphocyte signaling for immunotherapy

Lymphocytes are central orchestrators of immune responses, integrating signals from activating and inhibitory receptors, cytokines, and metabolic pathways to determine cell fate and function. Over the past decades, fundamental studies of lymphocyte signaling have revealed highly dynamic molecular networks controlling activation and subsequent effector responses. Specifically, insights into T lymphocyte signaling pathways have provided the mechanistic foundation for major breakthroughs in immunotherapy, including checkpoint blockade and chimeric antigen receptors (CARs). Despite remarkable clinical successes of T cell-based therapies, many patients fail to achieve durable responses, highlighting the need for a deeper understanding of signaling mechanisms that govern lymphocyte cell functionality. Beyond conventional αβ T cells, alternative lymphocyte populations, including NK, γδ T, iNKT, and MAIT cells, are emerging candidates for next-generation cellular immunotherapies. Bridging fundamental lymphocyte signaling research with translational approaches is therefore essential for the development of safer and more effective immunotherapeutic strategies.T cell-based immunotherapies have revolutionized the treatment of cancer and are increasingly used for treatment of autoimmune diseases. However, many patients fail to achieve durable clinical responses, while others experience severe adverse events. A major challenge in the field is to understand how the molecular mechanisms governing lymphocyte functions shape therapeutic outcomes. Fundamental signaling research is critical for identification of molecules or molecular mechanisms that can be targeted to improve efficacy or safety of immunotherapies. Current signaling research discovers new signaling enzymes and adaptors as well as their post-translational modifications, and describes how their assembly and sub-cellular localization regulate lymphocyte functions. Moreover, novel insights into cross-talk between distinct signaling pathways provide better understanding and control of different aspects of T cell activation and differentiation, such as effector responses, exhaustion, memory formation, and immune tolerance. Recent advances in basic immunology and transformative technologies provide deeper mechanistic insights into signaling networks and enable the rational engineering of diverse lymphocyte populations, whose distinct signaling architectures and effector programs must be considered for the development of safer and more effective cellular immunotherapies.This Research Topic will explore how fundamental insights into lymphocyte signaling can inform the development, optimization, and clinical translation of immunotherapies. We welcome contributions addressing the mechanisms that regulate lymphocyte activation, function, and manipulation. To capture the breadth of this field, submissions will be organized into three complementary sections:1. Manipulating Lymphocytes: CARs, TILs, Technological Advances, and Preclinical Models This section focuses on translational and technological strategies to engineer and harness lymphocyte function for therapeutic purposes, including chimeric antigen receptor (CAR) design and engineering, tumor-infiltrating lymphocyte (TIL)-based therapies, genome editing and functional genomic screens, single-cell and spatial multi-omics, imaging, structural and computational approaches, synthetic biology, and immune cell engineering. Studies employing preclinical models to evaluate the efficacy, persistence, and safety of engineered or manipulated lymphocyte products are particularly encouraged.2. Alternative Lymphocyte Populations for Immunotherapy and Immune Regulation This section welcomes contributions on regulatory and unconventional lymphocyte populations, including regulatory T cells, NK cells, γδ T cells, iNKT cells, MAIT cells, and innate lymphoid cells. Emphasis will be placed on their distinct signaling networks, functional properties, and potential for next-generation cell-based immunotherapies. Studies addressing their therapeutic use in cancer, infectious, autoimmune, and inflammatory diseases, as well as strategies to restore immune tolerance, improve efficacy, or reduce immune-related adverse events, are particularly encouraged.3. Lymphocyte Function and Signaling in the Context of Immunotherapy This section welcomes studies on the molecular and cellular mechanisms that regulate lymphocyte activation, differentiation, and effector function, particularly within the context of unconventional T cells as platforms for CAR-T therapy. Rather than general reviews of T cell signaling in isolation, we welcome studies addressing signaling mechanisms — including TCR signaling, co-stimulatory and co-inhibitory pathways, immune synapse organization, signaling adaptors and enzymes, cytokine signaling, metabolic regulation, and mechanotransduction and signal integration — when framed within the section’s other two broad topics. Topic editors: Javier Casas, Luca Simeoni, Konstantina Nika, Joanna Brzostek Source: https://www.frontiersin.org/research-topics/84574/decoding-and-rewiring-lymphocyte-signaling-for-immunotherapy