Reprogramming the Tumor Immune Microenvironment: Strategies to transform Cold Tumors into Hot

Cancer immunotherapy has entered a transformative era, providing durable benefits to many patients. However, a substantial subset of malignancies remains resistant due to their immunologically “cold” tumor microenvironments (TMEs), which are defined by limited infiltration of cytotoxic CD8⁺ T cells, impaired antigen presentation, attenuated interferon signaling, and the presence of immunosuppressive stromal and myeloid populations. These features collectively hinder immune recognition and limit the efficacy of immune checkpoint blockade (ICB) and other immunotherapies that rely on pre-existing antitumor T-cell activity.The TME represents a highly dynamic and plastic ecosystem, influenced by tumor intrinsic oncogenic pathways, host immune responses, metabolic stresses, and therapeutic pressures. Immune cold phenotypes can originate from diverse and often interrelated mechanisms, including mutation or epigenetic repression of antigen presentation machinery components, metabolic reprogramming that creates nutrient competition and hypoxia, and physical exclusion of T cells through aberrant angiogenesis and extracellular matrix remodelling. The enrichment of suppressive cellular subsets such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and M2 polarized tumor associated macrophages (TAMs) further establishes an immunoregulatory milieu dominated by IL 10, TGF β, and VEGF, thereby reinforcing tumor immune evasion.Multiple oncogenic signaling cascades, including WNT/β catenin, PI3K/AKT/mTOR, KRAS, MYC, and PTEN loss, have been implicated in promoting immune exclusion through modulation of chemokine gradients, suppression of type I interferon responses, and inhibition of dendritic cell recruitment. Consequently, strategies to convert immune cold tumors into immune hot, inflamed, and therapy responsive states are an urgent focus in cancer research.This Research Topic aims to highlight cutting edge research on the cellular, molecular, and systems level determinants of immune cold TMEs, while showcasing emerging strategies to reprogram these tumors toward immune activation and therapeutic responsiveness. We invite submissions that bridge fundamental mechanisms and translational applications to inform the next generation of precision immunotherapies.Topics of interest include, but are not limited to:• Mechanisms underlying immune exclusion and immune cold phenotype development• Crosstalk between oncogenic signaling pathways and antitumor immune responses• Epigenetic regulation of tumor antigenicity and MHC expression• Oncolytic viruses and immunogenic cell death as tools to inflame the TME• Radiotherapy, chemotherapy, and targeted therapy as in situ vaccination strategies• Biomaterial and nanoparticle-based systems for localized immune modulation• Multi-omics, spatial, and single cell analyses of TME heterogeneity and evolution• Biomarker discovery for predicting and monitoring immunotherapy response• Rational combination therapies that integrate immune checkpoint blockade with TME modifying interventionsSubmissions may include original research, brief reports, reviews, mini reviews, methods papers, or perspectives. Through interdisciplinary collaboration across immunology, systems biology, oncology, and bioengineering, this Special Issue seeks to advance mechanistic understanding and translational breakthroughs in overcoming tumor immune resistance.Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases, which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal. Topic editors: NAGESH KISHAN PANCHAL, Gaurav Sharma, Ajit Roy Source: https://www.frontiersin.org/research-topics/79994/reprogramming-the-tumor-immune-microenvironment-strategies-to-transform-cold-tumors-into-hot