Cannabidiol Activates Integrated Stress Response Signaling and Immune Trafficking Programs in an A375 Melanoma–Jurkat T Cell Coculture Model: A Multi-Omics Analysis

Cannabidiol (CBD) is a nonpsychoactive cannabinoid with emerging anticancer and immunomodulatory properties; however, its systems-level mechanisms in tumor-associated immune cells remain incompletely defined. Here, we investigated CBD in a melanoma-T cell coculture model using integrated transcriptomic and proteomic analyses. At a subcytotoxic concentration (10 μM), CBD selectively induced apoptosis in melanoma while preserving T-cell viability and enhancing IL-2 secretion. RNA sequencing revealed coordinated activation of stress-adaptive, immune activation, and trafficking programs, including modulation of T-cell receptor signaling and cytokine networks. Data-independent acquisition proteomics identified activation of eukaryotic initiation factor 2 (EIF2) signaling, a central node of the integrated stress response (ISR) linking redox and endoplasmic reticulum stress to translational control. Multiomics integration converged on immune cell trafficking as a consistent outcome, with upregulation of ICAM1, ITGB1, and associated adhesion-related proteins. These findings suggest ISR-dependent translational reprogramming as a putative mechanistic axis by which CBD reshapes T-cell function in the melanoma microenvironment. Our study provides pharmacological insight into how CBD modulates tumor-immune interactions and suggests potential utility as an adjunct immunomodulatory agent in melanoma.