TLS manipulation and immunotherapy in pancreatic cancer face significant mechanistic and regulatory uncertaintiesUnderstanding tumor structures could help treat pancreatic cancer

Pancreatic cancer is a highly malignant neoplasm with a poor prognosis. The low immunogenicity of the tumor, strong immunosuppression in the tumor microenvironment (TME), and a dense tumor stroma contribute to this outcome. As a result, it is crucial to remodel the pancreatic cancer immune microenvironment to turn “cold” tumors into “hot” ones. The presence of tertiary lymphoid structures (TLS) in the TME is linked to improved prognosis and better patient outcomes. Nevertheless, the complexity of TLS biology presents several critical research gaps. Foremost, among these is the limited mechanistic understanding of how specific components of TLS--such as distinct immune cell subsets, stromal elements and their molecular interactions contribute to either beneficial or adverse clinical outcomes. Furthermore, the temporal dynamics governing TLS induction, maturation, maintenance, and resolution in response to different therapeutic modalities remain poorly elucidated. Another significant area of uncertainty pertains to the precise regulatory pathways that modulate TLS function within the immunosuppressive tumor microenvironment of pancreatic cancer. The classical maturation model of TLS describes a linear development. Based on recent advances in the evolution of TLS, we propose the concept of TLS life cycle in this review which included the tissue-resident memory phase. The mechanisms that direct TLS induction, maturation, maintenance, and resolution after various therapies are then addressed. We also discuss the identification and detection of TLS and elaborate on TLS prognostic value. We synthesize in detail the relationship between TLS and the response to therapy in PDAC. Finally, we present some preclinical evidence favoring the manipulation of TLS function and evolution within the immunosuppressive tumor microenvironment of PDAC.