Mechanistic Foundations of KRAS-Driven Tumor Ecosystems: Integrating Crosstalk among Immune, Metabolic, Microbial,...

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated RAS GTPase, implicated in approximately 20% of all cancers.
• The tumor microenvironment (TME) is a complex ecosystem of cellular and non-cellular components that influences tumor initiation, progression, and therapeutic response.
• Distinct TME compositions are associated with wild-type versus oncogenic KRAS, and TME alterations occur during KRAS-targeted treatments.

Purpose of the Study:

• To review key developments and challenges in KRAS inhibitor research.
• To systematically evaluate how KRAS mutations influence the TME, including immunosuppression, metabolic interactions, stromal remodeling, and microbiome dysbiosis.
• To explore therapeutic strategies targeting TME interactions in KRAS-mutated cancers.

Main Methods:

• Literature review synthesizing preclinical and clinical studies.
• Systematic evaluation of mechanistic insights into KRAS-TME crosstalk.
• Exploration of therapeutic vulnerabilities and combination strategies.

Main Results:

• KRAS mutations orchestrate immunosuppressive TME niches, metabolic symbiosis, stromal remodeling, and microbiome dysbiosis.
• KRAS-targeted therapies induce TME rewiring, presenting both challenges and opportunities.
• Distinct TME landscapes are observed between wild-type and oncogenic KRAS variants.

Conclusions:

• Deciphering KRAS-dependent TME architectures is a critical area for precision oncology.
• Targeting TME interactions, through combinations with KRAS inhibitors, offers promising therapeutic avenues.
• Further research into KRAS-TME crosstalk is essential for improving cancer treatment outcomes.