Emerging Precision Therapeutic Strategies in Pancreatic Ductal Adenocarcinoma: KRAS Targeting, DDR Vulnerabilities, Immune Redirection, and Tumor Microenvironment Remodeling

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.

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

Overcoming cancer resistance in pancreatic cancer: toward dynamic precision oncology

Advances in KRAS-Targeted Therapies for Pancreatic Cancer

The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing globally, and PDAC remains one of the deadliest malignancies, primarily because of late-stage presentation at diagnosis and limited effective therapies. KRAS mutations are present in approximately 88–92% of PDAC cases, making KRAS an important therapeutic target in PDAC, despite its long-standing historical classification as being “undruggable.” This review comprehensively examines the role of KRAS in pancreatic cancer and summarizes both indirect and direct KRAS-targeted therapeutic strategies, including downstream pathway inhibition, metabolic targeting, and emerging direct KRAS inhibitors. The ongoing clinical trials are essential for establishing the efficacy of these emerging therapies, which are poised to gradually transition into clinical practice and ultimately improve patient outcomes. A major challenge with KRAS-targeted therapy is drug resistance, which occurs through both on-target and bypass mechanisms, but emerging combination strategies targeting parallel pathways show promise. Combination approaches involving chemotherapy, immunotherapy, PRMT5 inhibition, and tumor microenvironment targeting are being actively studied to overcome resistance. Overall, KRAS-directed therapies represent a significant and evolving advancement with the potential to improve outcomes in pancreatic cancer.

Engineering strategies to address immune and delivery barriers in pancreatic ductal adenocarcinoma: a barrier-matched translational framework

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely owing to profound therapeutic resistance driven by tumor heterogeneity, a highly immunosuppressive tumor microenvironment (TME), dense desmoplastic stroma, immune exclusion, and impaired antitumor immune surveillance. Although conventional chemotherapy provides limited clinical benefit, immune-based therapies have shown modest efficacy in unselected PDAC, highlighting the need for strategies that overcome the biological barriers underlying immune resistance. Recent advances in precision medicine and bioengineering have generated a diverse range of therapeutic platforms aimed at remodeling the PDAC ecosystem. This review evaluates oncolytic virotherapy, gene-editing technologies, engineered immune-cell therapies, nanotechnology-enabled delivery systems, and artificial intelligence (AI)-assisted precision oncology according to the PDAC barriers they are intended to address and the maturity of the supporting evidence. Oncolytic viruses may enhance tumor immunogenicity and reshape suppressive immune niches, whereas gene editing and engineered cellular therapies provide opportunities to target oncogenic vulnerabilities, improve immune-cell function, and overcome antigenic and stromal constraints. Nanotechnology-based platforms can modify tissue access, payload exposure, and local immune modulation in selected models, whereas AI approaches support molecular and spatial stratification and generate treatment-prioritization hypotheses. Most supporting evidence remains preclinical or early phase, and no platform class has established broad comparative clinical benefit in unselected PDAC. Translation remains constrained by intratumoral heterogeneity, delivery limitations, safety, manufacturing complexity, and insufficient predictive biomarkers. Translation will depend on biomarker-defined enrollment and on linking administered dose to tumor exposure, target engagement, biological activity, safety, and the added benefit of the investigational component. We therefore present a barrier-matched development framework rather than a validated treatment-assignment algorithm.

RAS signaling and remodeling of the immune microenvironment in pancreatic ductal adenocarcinoma: implications of emerging RAS-targeted therapy

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Its poor prognosis is closely related to early invasion, extensive stromal deposition, and a strongly immunosuppressive tumor microenvironment. Mutant KRAS is a major driver of PDAC initiation and progression, but its effects are not limited to cancer-cell proliferation. Increasing evidence indicates that oncogenic RAS signaling also alters the surrounding microenvironment by affecting fibroblast activation, extracellular matrix production, antigen presentation, myeloid-cell infiltration, and inflammatory cytokine signaling. These changes can restrict antitumor immune responses and may contribute to treatment resistance. As direct RAS-targeted agents move into clinical development, their effects on tumor immunity have become increasingly relevant. By integrating RAS-driven stromal and immune remodeling with emerging allele-specific and multi-selective RAS therapies, this Mini Review bridges mechanistic and clinical perspectives that are often discussed separately. This framework highlights the rationale for combining RAS inhibitors with immunotherapy and other microenvironment-targeted treatments.