The stroma plays a dual role in the tumour microenvironment (TME), where it can both promote or restrict tumour growth. These effects are significantly modulated by the presence of cancer-associated fibroblasts (CAFs), key components of the TME. The stroma and CAFs influence pancreatic cancer (PC) both physically and functionally. The physical impact involves the deposition of a wall-like matrix, creating a solid barrier that prevents the escape of materials from the inside and the entry of substances from the outside. Functionally, the stroma influences PC treatment through crosstalk between CAFs, cancer cells, and immune cells. Transformation of the “CAFs wall”, however, may reduce the original benefit of limiting PC metastasis. In this review, we found that targeting the CAFs and designing novel carriers allowing the entry of drugs or therapeutic agents into the TME are alternative strategies to effectively treat PC. This article aims to provide a specific review focusing on the possibly therapeutic markers and its novel therapeutic strategies of CAFs in PC, discussing the concise treatment methods and its new challenging in current advanced researches.