To mitigate such off-target risks, emerging strategies include: (1) nanoparticle-based delivery systems that restrict drug distribution to T cells within the tumor microenvironment; (2) prodrug formulations activated by tumor-specific enzymes or metabolic conditions; (3) CRISPR/dCas9-based epigenetic editing, enabling locus-specific modulation of exhaustion-related genes (e.g., PDCD1, TOX); and (4) temporal control of therapy, aligning epigenetic modulation with specific T cell differentiation windows to preserve progenitor pools. Here, PDCD1 is linked to neoplasm.