Antimicrobial Peptides Induce Cell Death in Marginal Zone Lymphoma Models Resistant to Targeted Therapies

ABSTRACT Introduction Marginal zone lymphoma (MZL) is an indolent yet incurable B‐cell malignancy in which targeted agents such as BTK and PI3K inhibitors frequently fail due to resistance or toxicity. Antimicrobial peptides (AMPs), evolutionarily conserved effectors of innate immunity, possess selective cytotoxicity against malignant cells by exploiting tumor‐specific membrane alterations. Methods Peptides were synthesized and tested for their anti‐proliferative activity in MZL cell lines. Results We evaluated the antitumor activity of seven natural AMPs, including Antarctic fish–derived trematocines and chionodracine variants, and amphibian temporins, against MZL cell lines (VL51, Karpas1718) and derivatives resistant to BTK, PI3Kδ, or PI3Kα/δ inhibitors. Among them, W‐trematocine and temporin L demonstrated potent dose‐dependent cytotoxicity with IC 50 values of 5.7–10 µM, maintaining full activity in all resistant models. Other peptides showed moderate activity, while chionodracine‐1 was inactive. Notably, W‐trematocine displayed minimal toxicity toward nonmalignant cells in prior studies, underscoring its selectivity. AMP‐mediated killing, driven by membrane disruption and non‐apoptotic death pathways, bypassed conventional resistance mechanisms, suggesting therapeutic potential in relapsed/refractory disease. Conclusion Our findings highlight natural AMPs as promising candidates for development in drug‐resistant MZL, warranting further optimization and preclinical validation.