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.
Abstract
The RAS/mitogen-activated protein kinase (MAPK) pathway is a pivotal oncogenic driver in numerous malignancies, most prominently pancreatic ductal adenocarcinoma, colorectal carcinoma, non-small cell lung cancer, and melanoma. The emergence of direct KRAS inhibitors, pan-RAS inhibitors, and agents targeting downstream signaling pathways (including MEK and ERK) has profoundly reshaped the therapeutic landscape. However, durable clinical responses remain scarce, owing to profound, rapid, and adaptive resistance mechanisms that extend far beyond tumor cell-intrinsic pathways. Over the past five years, accumulating evidence has unequivocally established that the tumor microenvironment (TME)—particularly its immune components—plays a key role in driving this resistance. This review synthesizes recent advances in understanding how specific TME constituents, including immune cells, cancer-associated fibroblasts (CAFs), and the extracellular matrix (ECM), interact with tumor cells to promote escape from pathway inhibition. We examine bidirectional signaling induced by therapy, consequent tumor cell plasticity, and the formation of a protective niche. Finally, we outline rational combination strategies 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.
Ras/MAPK alterations drive roughly 40% of human cancers which vary in phenotype, aggressiveness, and response to therapy. This thesis asks how oncogenic Ras/MAPK signaling interacts with distinct components of the tumor microenvironment to drive therapy resistance in two cancer types. The negative regulator of Ras, Neurofibromin 1 (NF1), is altered in about 20% of tubo-ovarian high-grade serous carcinomas (HGSC). We use in vitro and in vivo models of ovarian cancer to study how cell-cell interactions between adipocytes and cancer cells impact therapy response. NF1 alteration exacerbates adipocyte-mediated resistance to standard-of-care chemotherapy. Downstream of Ras, activating mutations in the BRAF kinase are present in over half of cutaneous melanoma cases. Specifically, BRAF^[V600E] hyperactivates downstream MAPK signaling, which is the target of several generations of small-molecule inhibitors. MAPK-targeted therapies show initial efficacy in patients, but acquired resistance is a major clinical threat. Focusing on the role of the immune compartment in treatment-refractory melanoma, we show that targeting the novel immune checkpoint, P-selectin glycoprotein ligand-1 (PSGL-1), delays relapse to BRAF/MEK-targeted therapy in pre-clinical models. Combined BRAF/MEK and PSGL-1 targeting provides a durable anti-tumor response through enhanced functionality and a memory-like phenotype in CD8⁺ T cell subsets. Together, these studies address how tumor-cell intrinsic and extrinsic factors interact under the selective pressure of therapy in Ras/MAPK-altered solid tumors. We provide insight on how genetic alterations affect interactions between cancer cells and their environment and how these dynamics reveal resistance mechanisms that can be exploited for therapeutic benefit.
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.
Rawan Salih, F. Sirajudeen, Mohamed Rahmani· Journal of Advanced Research· 0 citations
KRAS mutations are among the most prevalent oncogenic drivers in human malignancies and are increasingly recognized as critical determinants of tumor progression, immune evasion, and therapeutic resistance. Beyond its canonical role in promoting oncogenic signaling, accumulating evidence indicates that KRAS functions as a regulator of the tumor immune microenvironment, influencing antigen presentation, inflammatory signaling, metabolic adaptation, stromal remodeling, and responsiveness to immunotherapy. This review synthesizes current knowledge regarding the biological and immunological consequences of oncogenic KRAS across major cancer types, including non-small cell lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma, with emphasis on the mechanisms by which KRAS-driven tumors establish and maintain immunosuppressive microenvironments. Recent advances in immunopeptidomics and precision immuno-oncology have identified KRAS-derived neoantigens that can be targeted through T-cell receptor-engineered therapies, bispecific antibodies, and therapeutic vaccines. Concurrently, the clinical development of direct KRAS inhibitors, including sotorasib and adagrasib, has demonstrated meaningful antitumor activity while revealing adaptive resistance mechanisms that frequently limit durable responses. Emerging evidence suggests that effective therapeutic strategies will require integrating KRAS-targeted therapies with immune checkpoint blockade and other immunomodulatory approaches to overcome tumor-intrinsic and microenvironment-mediated resistance. Collectively, 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.
M. Ashrafizadeh, Noushin Nabavi, Yifei Xu· Cancer Biome and Targeted Th...· 0 citations
Oncogenic
KRAS
mutations rank among the most prevalent driver alterations in human malignancies, reaching near-universal frequency (~98%) in pancreatic ductal adenocarcinoma (PDAC) and high prevalence in colorectal cancer (CRC, ~52%) and lung adenocarcinoma (LAC, ~32%). Beyond their canonical roles in promoting cell-intrinsic proliferation and survival through the MAPK/ERK and PI3K/AKT cascades, KRAS mutations actively sculpt a profoundly immunosuppressive tumor microenvironment (TME), which constitutes a major barrier to both targeted therapy and immunotherapy. Through coordinated programs encompassing inflammatory cytokine secretion, downregulation of antigen presentation machinery, tumor-associated macrophage (TAM) reprogramming, myeloid-derived suppressor cell (MDSC) expansion, and PD-L1 upregulation, KRAS-mutant tumors establish robust immune exclusion. These programs are further stratified by co-mutations in
STK11
,
KEAP1
, and
TP53
, which define distinct immune phenotypes ranging from inflamed to profoundly immune-excluded “cold” tumors. The recent approval of covalent KRAS G12C inhibitors, sotorasib and adagrasib, has revealed that targeted KRAS blockade can remodel the TME toward an immunostimulatory state, providing a mechanistic rationale for combining KRAS-directed agents with immune checkpoint blockade, STING agonists, and neoantigen vaccines. This mini-review synthesizes the current knowledge of KRAS-immune crosstalk, highlights existing controversies and research gaps, and evaluates emerging combination strategies designed to convert immune exclusion into durable anti-tumor immunity.
Vasudevan Ramachandran, H. Koyou, Siddarth Raajasekar et al.· Frontiers in Oncology· 0 citations
The extracellular signal-regulated kinases 1 and 2 (ERK1/2) play central roles in the mitogen-activated protein kinase (MAPK) pathway and have emerged as critical regulators of tumorigenesis. Aberrant ERK1/2 signaling is frequently observed in cancers such as melanoma, pancreatic cancer, and colorectal cancer. This review outlines the historical milestones in ERK1/2 research, from their discovery and structural characterization to their identification as oncogenic drivers and therapeutic targets. We detail the ERK1/2 signaling network, highlighting key upstream regulators, including rat sarcoma (RAS), rapidly accelerated fibrosarcoma (RAF), and mitogen-activated protein kinase kinase (MEK), along with downstream substrates that mediate diverse oncogenic processes. Therapeutic approaches aimed at ERK1/2 currently fall into two main classes: small-molecule inhibitors with single-target specificity and those designed to simultaneously act on dual targets, along with combination therapies designed to overcome resistance and improve efficacy. Furthermore, we explore innovative approaches, including proteolysis-targeting chimeras (PROTACs), autophagy-targeting chimeras (AUTACs), and antibody-drug conjugates (ADCs), which offer promising avenues for selectively modulating ERK1/2 activity. By integrating mechanistic insights with clinical development trends, this review underscores the potential of ERK1/2-targeted therapies in precision oncology.
Zhiqi Peng, Yuqi Fu, Yanmei Chen et al.· Medicinal research reviews (...· 0 citations
BACKGROUND
Tumor recurrence, metastasis, and treatment resistance represent core challenges in clinical oncology closely associated with the complex and dynamic tumor microenvironment (TME). Endothelial cells (ECs), key components of the TME, have functions that extend far beyond the traditional concept of tumor angiogenesis. In recent years, extensive research has revealed that ECs perform endocrine and paracrine functions by secreting angiocrine factors. These factors have been shown to contribute to tumor progression through multiple mechanisms, including remodeling of the tumor vascular niche, tumor immune suppression, metabolic reprogramming, and chemotherapy resistance. Therefore, a deeper understanding of the functional characteristics and regulatory mechanisms of angiocrine factors is crucial for identifying effective therapeutic targets in cancer.
MAIN BODY
This review integrates research advances on angiocrine factors associated with tumor progression, categorizing them into several key functional domains on the basis of their biological characteristics. We summarize the core signaling pathways regulated by angiocrine factors, including the Notch and Wnt pathways, and their crosstalk networks. We further elucidate the regulatory role of angiocrine factors in endothelial metabolism. Additionally, we explore the multifaceted functions of angiocrine factors in tumor dormancy, metastasis (tumor metastasis mediated by endothelial necroptosis), stemness maintenance, and immune suppression. Notably, this review highlights the complex crosstalk between ECs and tumor cells (TCs), as well as the roles of Notch and Wnt signaling pathways in vascular formation and endothelial metabolic. Finally, we discuss the current clinical limitations of anti-angiogenic therapies and combination treatment strategies, while highlighting the therapeutic potential and challenges of a "one-target, multiple-effects" approach.
CONCLUSION
Angiocrine factors are central regulatory mediators that coordinate tumor progression. The complexity and redundancy of the angiocrine factor networks is not only the root of limitations in anti-vascular therapies but also present opportunities for "one-target, multiple-effects" strategies. Rapid advances in single-cell transcriptomics, spatial transcriptomics, and lineage tracing technologies now provide powerful tools to decipher the spatiotemporal heterogeneity of vascular secretory factors and to track the clonal evolution and functional transitions of endothelial cells and their progenitor cells. These advances offer the potential to precisely identify key therapeutic targets, facilitating the development of novel anti-angiogenic strategies.
Gaili Ji, Yaping Wang, Xiaoxue Li et al.· Journal of Translational Med...· 0 citations