Immune reprogramming in cancer: from immune exclusion to durable response

Immunotherapy has fundamentally transformed oncology, establishing a new pillar of cancer treatment alongside surgery, chemotherapy, and radiation. While immune checkpoint inhibitors (ICIs) have delivered unprecedented durable responses in immunogenic tumor types such as melanoma and lung cancer, a significant clinical challenge remains: the majority of patients with solid tumors exhibit primary resistance or develop acquired resistance. This issue is particularly acute in "cold" or immune-excluded tumors, where the tumor microenvironment (TME) creates physical and metabolic barriers to immune infiltration. Current research indicates that overcoming these barriers requires more than simple checkpoint blockade; it demands a comprehensive understanding of the cellular "wiring" that dictates immune exclusion. By exploring the dichotomy between hot and cold phenotypes across different histologies, we can identify universal principles of resistance. This Research Topic aims to explore the mechanisms of immune evasion and the novel strategies required to reprogram the TME for therapeutic success.


The primary goal of this Research Topic is to dissect the mechanisms governing immune exclusion and identify actionable strategies to "reprogram" the tumor microenvironment (TME) toward a responsive state. The field is currently shifting focus from T-cell intrinsic mechanisms to the broader ecosystem that supports the tumor, including myeloid cells, cancer-associated fibroblasts (CAFs), and the vasculature.

We aim to tackle the problem of resistance by bridging the gap between basic immune biology and clinical application. Specifically, we seek to highlight recent advances in spatial biology, immunometabolism, and systemic immune conditioning that are decoding the architecture of resistance. This collection will focus on how established "cold" tumors can be primed for response through novel combinations, targeted modulation of the stroma, or metabolic interventions. By integrating findings across diverse tumor types—from highly responsive hot tumors to notoriously immune-privileged sites—this topic aims to uncover scalable strategies for immune reprogramming that lead to durable clinical benefit.


We welcome Original Research, Reviews, and Perspectives that address the transition from immune exclusion to active tumor elimination in any solid tumor malignancy. We specifically encourage mechanistic studies that offer translational insights into overcoming resistance.

Specific themes of interest include:

• Mechanisms of Exclusion: Cellular and molecular drivers of T-cell exclusion and seques-tration in "cold" tumors.

• TME Architecture: Spatial heterogeneity, tertiary lymphoid structures (TLS), and the role of the tumor stroma/CAFs.

• Systemic Reprogramming: The impact of systemic treatments (chemotherapy, ADCs) and host factors (microbiome, metabolism) on immune plasticity.

• Myeloid Biology: Reprogramming tumor-associated macrophages (TAMs) and MDSCs to support anti-tumor immunity.

• Novel Targets: Therapeutic strategies beyond PD-1/CTLA-4, including bispecific antibodies, vaccines, and metabolic modulators.

Please 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