Pancreatic ductal adenocarcinoma (PDAC) is a highly immunosuppressive malignancy. Despite advances in immunotherapy in general, response in PDAC remains hindered by its extremely complex tumour microenvironment (TME). Key effectors-cytotoxic lymphocytes (CTLs or CD8 T-cells) - are rendered dysfunctional in PDAC; compromising both endogenous immune responses and T-cell based therapies. To dissect the impact of PDAC-derived secretory factors on T-cell fitness, primary CTLs were activated in cancer conditioned media. Functional assays demonstrated reduced viability and impaired cytotoxic effector response in a dose-dependent manner as compared to healthy controls. Flow cytometric analysis of these lymphocytes revealed attenuated expression of activation markers and a sustained expression of inhibitory markers upon chronic stimulation. This suggested secreted factors from pancreatic cancers mediate dysregulation of activated T-cell signalling pathways and promote dysfunctional state of CTLs in PDAC tumours. Further, to identify universal immunosuppressive factors with broad therapeutic scope, we utilised bioorthogonal labelling to profile the secretome of 5 pancreatic cancer cell lines representing the distinct subtypes. Differential analysis of each PDAC line against the healthy pancreatic ductal line revealed that immunomodulatory proteins were upregulated in the PDAC secretome, highlighting potentially targetable mediators of immune suppression. Using bioorthogonal chemistry and metabolic labelling, we performed temporal proteomic profiling of these T-cells, to capture the dynamic changes in newly synthesized proteins and phosphorylated proteins during different phases of CTL activation. This approach revealed specific pathways disrupted by PDAC secretory factors, and provided a mechanistic resolution to understand the suppressive force on T-cell function. In conclusion, this study integrates temporal proteomics and secretome profiling to uncover PDAC-derived factors that impair CTL functions and pinpoint disrupted pathways in dysfunctional T-cells for targeted intervention. These finding go beyond foundation to justify targeting secretory components of PDAC to restore T-cell fitness and enhance immunotherapeutic efficacy.