胰腺癌(PC)的特点是其极具侵略性,在全球新发癌症病例数中排名第14位。然而,由于其复杂性,它在全球最致命的癌症名单中排名第七。PC的发病机制涉及到几个复杂的过程,包括与肥胖等危险因素相关的家族遗传因素,糖尿病,慢性胰腺炎,和吸烟。KRAS等基因突变,TP53和SMAD4与产生胰腺病变的恶性细胞的出现有关,因此,癌症。在这种情况下,一些疗法用于PC,其中之一是免疫疗法,这在各种其他类型的癌症中非常有希望,但由于各种抗性机制导致免疫疗法效率下降,在PC的治疗中几乎没有反应。因此很明显,肿瘤微环境(TME)对耐药过程有巨大的影响,因为细胞和非细胞元素创造了免疫抑制环境,以致密的增生性基质与癌症相关的成纤维细胞为特征,胰腺星状细胞,细胞外基质,和免疫抑制细胞。与之相关的是TP53基因突变和作用于T细胞的免疫抑制因子,导致CD8+T细胞的短缺和激活标记如干扰素-γ的有限表达。这样,找到新的策略,使它有可能操纵抗性机制是必要的。因此,技术,如使用TME调节剂阻断受体和产生抗性的基质分子,在特定地区使用遗传操作,比如microRNA,与T细胞相关的外在和内在因素的调节,and,最重要的是,结合这些调制技术的治疗模型构成了PC治疗的有希望的未来。因此,本研究旨在阐明PC对免疫疗法耐药的主要机制以及操纵这一过程的新方法,为癌症患者提供更有效的治疗,因此,降低这种侵袭性癌症的致死率。
Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53, and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.