Mechanistic Insights and Therapeutic Reprogramming of the Tumor Immune Microenvironment

The field of tumor immunology is increasingly focused on the tumor immune microenvironment (TIME), a complex and evolving network comprising malignant cells, stromal elements, and diverse immune populations. Recent advances in immunotherapies—including checkpoint inhibitors and engineered cellular therapies—have profoundly influenced oncology, yet only a subset of patients experiences durable clinical benefit. Several limiting factors underpin this challenge, such as immune exclusion from tumor sites, robust immunosuppressive signaling, altered antigen presentation, and the metabolic and epigenetic barriers orchestrated by the tumor and its environment. Although significant progress has been made in profiling the cellular and molecular constituents of the TIME, a molecularly detailed understanding of the mechanisms that establish, maintain, and reshape this microenvironment remains incomplete. This knowledge gap hampers the rational design of therapies that can effectively and sustainably modulate anti-tumor immunity.

This Research Topic aims to deepen mechanistic insights into the establishment and dynamic remodeling of the TIME, with a focus on developing actionable frameworks for immunotherapeutic intervention. The primary objectives are to elucidate how molecular and cellular pathways—including cytokine/chemokine signaling, immunometabolic crosstalk, antigen processing, immune checkpoint regulation, as well as epigenetic and stress-adaptive responses—contribute to immune evasion and therapeutic resistance. We also seek to integrate systemic factors such as metabolism, endocrinology, and novel multi-omics biomarkers to bridge cancer immunology with broader aspects of host physiology and comorbid conditions. Ultimately, this Research Topic will highlight strategies to rationally reprogram the TIME, support discovery of next-generation combination therapies, and accelerate clinical translation—particularly in tumor types characterized by immune exclusion and poor prognosis.

The Scope of this Research Topic encompasses both fundamental and translational explorations, but is limited to studies delivering mechanistic validation, molecular readouts, or innovative immunotherapy platforms for TIME remodeling and resistance reversal. We welcome research addressing, but not limited to, the following themes:

• Mechanisms of immune–tumor and immune–stroma interactions
• Cytokine, chemokine, and antigen presentation dynamics in TIME
• Immunometabolic and systemic metabolic regulation of tumor immunity
• Epigenetic, RNA-mediated, and stress-adaptive networks in immune evasion
• Multi-omics biomarker development and causal inference approaches in cancer immunology
• Platforms for programmable TIME remodeling (e.g., engineered cells, targeted delivery, biomaterials)
• Strategies to overcome immunotherapy resistance, with a focus on hepatobiliary and pancreatic malignancies