KRAS mutations as architects of the tumor immune microenvironment: implications for combination therapies

Oncogenic KRAS in Cancer Immunotherapy: From Oncogenic Signaling to Tumor-Immune Ecosystem Regulation

Current evidence supports a paradigm in which KRAS functions not only as an oncogenic driver but also as a regulator of tumor-immune interactions, shaping therapeutic responsiveness and providing opportunities for biomarker-guided and combination-based immunotherapy in KRAS-mutant cancers.

KRAS signaling networks, mutational heterogeneity, and emerging therapeutic strategies for cancer treatment

Kirsten rat sarcoma viral oncogene homolog (KRAS), a member of the small GTPase family, is the most frequently mutated RAS isoform in human cancers. It drives tumorigenesis and progression in various malignancies, including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC), and has long been considered an “undruggable” target. Recent advances in mutant-selective KRAS inhibition have reshaped this view, but therapeutic responses remain limited by adaptive resistance, tumor heterogeneity, and context-dependent signaling dependencies. This review focuses on how allele-specific biochemical properties, tissue context, and co-mutational backgrounds shape KRAS signaling output, tumor progression, therapeutic response, and resistance. We further discuss current diagnostic approaches and therapeutic strategies, ranging from direct mutant-selective inhibitors to pathway-targeted combinations, degraders, immunotherapies, RNA-based approaches, and exosome-mediated delivery. Finally, we highlight key challenges including adaptive resistance, tumor heterogeneity, allele-specific druggability, and the need for biomarker-guided combination strategies. Together, this review provides a framework for understanding KRAS-mutant cancers as biologically diverse diseases and for guiding the development of more precise and durable therapeutic strategies.

Unveiling and harnessing: the tumor microenvironment in RAS/MAPK pathway-targeted therapy

Rational combination strategies are outlined that simultaneously target the RAS/MAPK axis and key TME vulnerabilities, such as immunotherapy combinations, CAF reprogramming, and ECM normalization, to overcome stromal-mediated resistance and achieve deeper, more sustained clinical responses.

Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma: from Tumor Biology to Biomarker-Guided Strategies

The molecular underpinnings of the immune landscape in prostate cancer: decoding a “cold” tumor

Prostate cancer (PCa) remains a leading cause of cancer-related death in men, characterized by a notoriously immunosuppressive tumor microenvironment (TME) that renders it largely refractory to immune checkpoint inhibitors (ICIs). This “cold” tumor phenotype is orchestrated by a complex network of molecular mechanisms, rather than a simple absence of antigens. Here, we provide a focused review of the key molecular drivers enforcing immune evasion in PCa, moving beyond cellular descriptions to the underlying genomic and signaling aberrations. We dissect the roles of tumor-intrinsic oncogenic pathways, specifically the androgen receptor (AR) signaling axis, PTEN/PI3K/AKT activation, and loss of tumor suppressors like TP53 and RB1, in sculpting an immunosuppressive secretome. Furthermore, we explore the paradoxical role of genomic instability, where defects in mismatch repair (dMMR) and homologous recombination deficiency (HRD) create neoantigens but simultaneously foster immune exclusion through the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway and immunosuppressive cytokines. We discuss emerging controversies, including the immunostimulatory versus immunosuppressive duality of AR signaling and the role of the STING pathway in promoting a pro-metastatic inflammatory state. Critically, we highlight that many of these mechanistic insights are predominantly derived from preclinical models, and their direct translation to clinical responses remains an ongoing challenge. The field is also constrained by a lack of robust, validated predictive biomarkers beyond dMMR. Moreover, the mechanisms of immune evasion in treatment-emergent neuroendocrine prostate cancer (NEPC) represent a critical knowledge gap, hindering immunotherapy development for this aggressive variant. Future therapeutic strategies must pivot from a monotherapy paradigm to rationally designed molecular combinations that leverage our deepening understanding of these intricate mechanisms to convert the TME from an immune desert into an inflamed, ICI-responsive hub.

From KRAS inhibition to tumor adaptation: mechanistic layers of resistance and therapeutic strategies.

This review synthesizes current knowledge on KRAS resistance mechanisms and highlights emerging therapeutic strategies, including rational combination approaches, enhanced RAS pathway suppression, targeted protein degradation, and KRAS-directed immunotherapies.