LCP2 mediates SUV39H1-driven cellular senescence-related chemoresistance in natural killer/T-cell lymphoma.

Natural killer/T-cell lymphoma (NKTCL) is an aggressive haematological malignancy with poor prognosis, particularly in patients with relapsed/refractory (R/R) disease. The mechanisms underlying multidrug resistance in NKTCL remain unclear and present an urgent challenge that must be addressed during clinical treatment. Multidrug-resistant NKTCL models were established using adriamycin (ADM), and cellular senescence was confirmed by markers including P16, P21, and senescence-associated β-galactosidase (SA-β-gal). Proteomic sequencing of plasma from clinical patients and resistant cells identified LCP2 as a key protein. Phosphoproteomics, mass spectrometry, and co-immunoprecipitation analyses revealed LCP2's role in mediating senescence-associated chemoresistance. An in vivo ageing microenvironment model was used to assess whether targeting the LCP2-mediated axis could eliminate chemoresistant senescent cells. Results show that ADM-resistant NKTCL cells exhibited phenotypic and senescence features. Of these, LCP2 expression was significantly reduced in the plasma of R/R NKTCL patients and in chemoresistant cells, correlating inversely with senescence marker SA-β-gal. Moreover, LCP2 knockdown enhanced the chemoresistance, senescent-associated secretory phenotype secretion, and G0/G1 cell cycle arrest in NKTCL cells. Mechanistically, LCP2 deficiency activated the IQGAP2/LaminA/C/SUV39H1 axis, thus driving DNA damage, telomere stress-induced senescence, and facilitating the formation of an immunosuppressive microenvironment. Importantly, targeting this axis with Epitalon and Chaetocin can partially eliminate therapy-induced senescent cells, enhance response to chemotherapeutics, and alleviate the immunosuppressive microenvironment to a certain extent in vivo. In conclusion, this study is the first to uncover LCP2 as a critical biomarker of senescence-related chemoresistance in NKTCL, providing a theoretical basis for the clinical translation of senolytics for treating R/R NKTCL.