Cancer immunology research has increasingly focused on the complex interactions between oncogenic drivers, such as KRAS mutations, and the tumor microenvironment. KRAS mutations, which are pervasive in malignancies like pancreatic, colorectal, and lung cancers, have been shown to profoundly alter tumor cell behavior and the surrounding stroma, resulting in unique patterns of immune evasion. Although recent advances have illuminated the molecular underpinnings of KRAS-driven tumorigenesis, key questions remain regarding the specific mechanisms through which this oncogene manipulates immune signaling, antigen presentation, cytokine networks, and metabolic pathways to circumvent anti-tumor immunity.

Despite the success of immune checkpoint therapies in some settings, KRAS-mutant cancers often resist immunotherapy due to their capacity to shape suppressive and immune-deserted niches. Landmark studies using single-cell omics, spatial analyses, and functional modeling have begun to unravel the heterogeneity of these niches and how KRAS variants, together with co-occurring mutations, modulate both immune exclusion and immunogenicity. However, substantial knowledge gaps persist in understanding how these integrated programs can be therapeutically targeted, and how a systems-level view of KRAS-driven immune escape could guide the design of next-generation immunotherapies.

This Research Topic aims to advance the understanding of how oncogenic KRAS signaling interfaces with the tumor microenvironment to drive immune evasion, and to explore how these vulnerabilities might be exploited to improve patient outcomes. Central objectives include delineating KRAS-dependent circuits of immune escape, charting the metabolic and stromal reprogramming that influences immune cell function, clarifying how intra-tumoral heterogeneity and variant-specific signaling impact immunogenicity, and defining innovative therapeutic strategies that re-sensitize tumors to immunotherapy. The Topic encourages the discovery and validation of new biomarkers and translational readouts that can better predict and track responses to immune-based interventions in the context of KRAS-mutant cancers.

This Research Topic will encompass studies focused on mechanistic, translational, computational, or clinical aspects of KRAS-mutant tumors and their immune microenvironments. Reviews and perspectives are also welcomed. To gather further insights in the boundaries of immunotherapy in KRAS-mutant cancers and their microenvironmental context, we welcome articles addressing, but not limited to, the following themes:

- Mechanisms of KRAS-dependent immune escape: antigen presentation, interferon signaling, and immunosuppressive cytokines/chemokines

- Microenvironmental reprogramming: metabolic rewiring, extracellular matrix remodeling, and the roles of stromal and myeloid cells

- Tumor heterogeneity and cell state dynamics: single-cell/spatial -omics, imaging, and computational modeling

Influence of KRAS allelic variants and co-mutations on immune interactions and therapy responsiveness

- Rational design and evaluation of combination therapies targeting both KRAS pathways and immune checkpoints or stroma

- Development of composite biomarkers, including genomic, transcriptomic, and spatial metrics, for predicting and monitoring immunotherapy response

Please note that manuscripts consisting solely of bioinformatics or computational analysis of public omics databases that are not supplemented by relevant functional validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic.

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Immunotherapy at the Interface of Oncogenic KRAS Signaling and the Tumor Microenvironment