肿瘤细胞治疗研究
英文原题：Emerging Precision Therapeutic Strategies in Pancreatic Ductal Adenocarcinoma: KRAS Targeting, DDR Vulnerabilities, Immune Redirection, and Tumor Microenvironment Remodeling.
Emerging Precision Therapeutic Strategies in Pancreatic Ductal Adenocarcinoma: KRAS Targeting, DDR Vulnerabilities, Immune Redirection, and Tumor Microenvironment Remodeling.
背景/目的：胰腺导管腺癌（PDAC）仍然是最致命的恶性肿瘤之一，其原因在于侵袭性的肿瘤生物学行为、普遍存在的治疗耐药、快速的适应性重编程以及深度免疫抑制的肿瘤微环境。
背景/目的：胰腺导管腺癌（PDAC）仍然是最致命的恶性肿瘤之一，其原因在于侵袭性的肿瘤生物学行为、普遍存在的治疗耐药、快速的适应性重编程以及深度免疫抑制的肿瘤微环境。本综述总结了KRAS靶向治疗、DNA损伤应答（DDR）导向策略、免疫重定向平台以及肿瘤微环境调控方面的最新进展。方法：我们对同行评议出版物、临床试验报告、试验注册库以及部分会议数据进行了叙述性综述，这些资料涉及PDAC新兴治疗策略。结果：KRAS靶向治疗，包括KRAS G12D选择性抑制剂和多选择性RAS(ON)抑制剂，已显示出显著的临床前活性及初步临床活性，同时揭示了多种适应性耐药机制。DDR导向方法正从BRCA突变疾病扩展至功能性同源重组缺陷、复制压力和合成致死。与此同时，双特异性抗体、T细胞衔接器和CAR-T细胞疗法已产生抗肿瘤活性的初步证据，尽管基质排斥、抗原异质性和免疫抑制仍是主要障碍。这些进展表明，PDAC的治疗耐药是一个动态过程，涉及相互关联的致癌、基因组、基质、代谢和免疫机制。结论：未来的进展将需要基于生物学信息的治疗框架，根据基线肿瘤生物学和治疗诱导的适应状态整合互补的治疗方式，并辅以纵向生物标志物和合理的临床试验设计。
Background/Objectives : Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies because of aggressive tumor biology, pervasive therapeutic resistance, rapid adaptive reprogramming, and a profoundly immunosuppressive tumor microenvironment. This review summarizes recent advances in KRAS-targeted therapies, DNA damage response (DDR)-directed strategies, immune-redirection platforms, and tumor microenvironment modulation. Methods : We conducted a narrative review of peer-reviewed publications, clinical trial reports, trial registries, and selected conference data addressing emerging therapeutic strategies for PDAC. Results : KRAS-targeted therapies, including KRAS G12D-selective and multi-selective RAS(ON) inhibitors, have demonstrated substantial preclinical and emerging clinical activity while revealing diverse mechanisms of adaptive resistance. DDR-directed approaches are expanding beyond BRCA-mutated disease toward functional homologous recombination deficiency, replication stress, and synthetic lethality. In parallel, bispecific antibodies, T-cell engagers, and CAR-T-cell therapies have generated preliminary evidence of antitumor activity, although stromal exclusion, antigen heterogeneity, and immune suppression remain major barriers. These advances indicate that therapeutic resistance in PDAC is a dynamic process involving interconnected oncogenic, genomic, stromal, metabolic, and immune mechanisms. Conclusions : Future progress will require biologically informed treatment frameworks integrating complementary therapeutic modalities according to baseline tumor biology and treatment-induced adaptive states, supported by longitudinal biomarkers and rational clinical trial design.
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