Immunotherapy Reimagined: Cell Death Signals and Non-Traditional Targets in the Tumor Microenvironment

Immunotherapy has transformed the treatment landscape for many cancers, yet its efficacy remains highly variable across tumor types and patient populations. A key under-explored frontier lies at the intersection of cell death and immune regulation. Tumor cell death, whether immunogenic or immunologically silent, shapes the TME in profound ways by modulating inflammation, antigen availability, and the recruitment as well as education of immune cells. This Research Topic aims to reframe cell death not as a terminal event, but as a central immunological determinant that can either promote anti-tumor immunity or facilitate immune evasion. In parallel, the collection will spotlight non-traditional immune regulators—such as lipid- and glycan-binding receptors, metabolic stress sensors, and alternative checkpoints—that influence how the immune system interprets the death of cancer cells. These molecules and mechanisms represent a promising, yet under-appreciated, therapeutic frontier. By curating diverse perspectives from across cancer immunology, cell death biology, and receptor-ligand signaling, we aim to catalyze new insights, identify actionable targets, and broaden the conceptual toolkit for researchers and clinicians working to advance immunotherapy.We invite the submission of original research articles and reviews that explore innovative immunotherapeutic strategies in the context of tumor cell death and non-traditional targets within the tumor microenvironment (TME). Articles may focus on damage-associated molecular patterns (DAMPs), non-apoptotic forms of cell death such as necroptosis, pyroptosis, and ferroptosis, as well as the immune consequences of efferocytosis. Beyond protein-focused mechanisms, studies investigating lipid- or glycan-associated death signals are especially encouraged. We also welcome contributions on emerging or understudied regulators of immune function in the TME, including scavenger receptors, phospholipid-binding and -modulating molecules, glyco-immune checkpoints, and non-canonical ligand-receptor interactions. Both human-based and preclinical model systems are appropriate.We welcome articles addressing, but not limited to, the following topics:• Immunogenic cell death and its consequences in the TME• Non-apoptotic cell death pathways (e.g., ferroptosis, necroptosis, pyroptosis)• Lipid and glycan signaling in immune regulation• Non-classical immune checkpoints and scavenger receptors• Biochemical, imaging, and systems-level approaches revealing new immunotherapeutic targets• Translational studies or early-phase therapies targeting these mechanismsPlease note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic Topic editors: David C Calianese, David Han Source: https://www.frontiersin.org/research-topics/75286/immunotherapy-reimagined-cell-death-signals-and-non-traditional-targets-in-the-tumor-microenvironment