Molecular Mechanisms of Immune Resistance in Pancreatic Cancer: An Update.

Pancreatic cancer is an exceptionally aggressive form of cancer with a poor prognosis, primarily due to several factors, one of which is the significant development of immune resistance. Despite new medical perceptions of the interaction between the immune system and tumour, experts have continually explored the molecular mechanisms of immune resistance in pancreatic cancer over the years but have not yet reached a complete understanding. Studying immune resistance is also fundamental because it gives us a better understanding of how to develop highly effective, individualised immunotherapeutic approaches. However, various characteristics can be used to describe the degree of immunological resistance. In the case of pancreatic cancer, the Tumour Microenvironment (TME) is specially structured in a way that it consists of stroma abundantly. Concurrently, it can regulate the secretion and expression of various immunosuppressants, like programmed death-ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), adenosine, and inosine that impairs the anti-tumour response attributed from the immune system, along with growth factors that contributes to the development of tumour growth. Besides, oncogenic pathways, such as TP53 and KRAS mutation and immunosuppressive cell populations, including T-regulating cells and myeloid-derived suppressor cells collaboratively suppress the immune activity, thereby inducing immune resistance. These complexities present significant challenges in designing effective treatments. Immune checkpoints and mechanisms such as PDL1- mediated MHC-1 downregulation, galectins, autophagy, TP53, and P2RX1-negative neutrophils also contribute to immune resistance. Hence, this review summarises the current knowledge regarding the underlying molecular mechanisms of immune resistance in pancreatic cancer, along with several existing molecular therapeutics and approaches to overcome these barriers.