Targeting Peripheral T-Cell Lymphomas with Chimeric Antigen Receptor Therapy: Mechanistic Challenges, Clinical Landscape and Future Engineering Perspectives

Peripheral T-cell lymphomas (PTCL) comprise a biologically diverse and clinically aggressive family of mature T/NK-cell neoplasms, for which outcomes remain poor in the majority of patients treated with conventional anthracycline-based frontline regimens. Contemporary classifications (WHO-HAEM5 and ICC) increasingly incorporate immunophenotypic and molecular information, underscoring that "PTCL-NOS" is not a single disease but rather a diagnostic umbrella that includes biologically distinct entities and molecular subgroups. Among these are the TBX21- and GATA3-driven PTCL-NOS subsets, the latter associated with inferior survival and a distinctive cytokine/microenvironmental program. These advances, many of which were shaped by long-standing contributions from the Bologna group, support a rational shift from empiric chemotherapy toward mechanism-based and immune-based interventions. CAR-engineered cellular therapies have revolutionized the care of B-cell malignancies, yet translation to PTCL has been delayed by lineage-specific barriers: (i) fratricide during manufacturing when targeting shared T-cell antigens (e.g., CD5, CD7), (ii) the risk of profound and prolonged T-cell aplasia (a markedly less "replaceable" toxicity than B-cell aplasia), and (iii) product contamination by malignant T-cells in autologous platforms. Recent progress in genome editing (CRISPR/Cas9 and base editing), intracellular antigen "blocking" strategies, and alternative effectors (allogeneic "universal" CAR-T, CAR-NK, and iPSC-derived platforms) has begun to address these obstacles at the manufacturing level, while their downstream clinical consequences (e.g., prolonged cytopenias, infectious risk and delayed immune reconstitution) remain incompletely resolved. Early-phase clinical trials now demonstrate clinically meaningful responses for select targets, particularly CD7, CD5, TRBC1 and CD30, for the pan-T targets. However, the strongest efficacy data remain largely derived from T-cell lymphoblastic malignancies (T-ALL/T-LBL), whereas evidence in mature PTCL remains limited and at an earlier stage, with target-specific differences in safety, immune reconstitution and relapse patterns. This review synthesizes the biological rationale for antigen selection in PTCL, the emerging clinical evidence for leading CAR targets, and the engineering strategies most likely to improve the therapeutic index. It also proposes an integrated hematology perspective on how CAR-based therapies might be positioned relative to transplant and evolving targeted agents in relapsed/refractory PTCL.