LCP2 mediates SUV39H1-driven senescence-related chemoresistance in NKTCL; Epitalon and Chaetocin enhance chemosensitivity.

Natural killer/T-cell lymphoma (NKTCL) is an aggressive haematological malignancy with poor prognosis, particularly in patients with relapsed/refractory (R/R) disease. A significant clinical challenge is the unclear mechanisms underlying multidrug resistance (MDR), which severely limits treatment efficacy. Cellular senescence, a state of irreversible cell cycle arrest, is increasingly recognized for its role in cancer progression and chemoresistance, but its specific drivers in NKTCL MDR, especially involving novel biomarkers, remain underexplored. Understanding these mechanisms is crucial for developing new therapeutic strategies.

Researchers established multidrug-resistant NKTCL models using adriamycin (ADM). Cellular senescence was confirmed via markers including P16, P21, and SA-β-gal. Proteomic sequencing of plasma from clinical R/R NKTCL patients and resistant cells identified LCP2 as a key protein. Phosphoproteomics, mass spectrometry, and co-immunoprecipitation analyses elucidated LCP2's role in mediating senescence-associated chemoresistance. An in vivo ageing microenvironment model was used to assess whether targeting the LCP2-mediated axis with Epitalon and Chaetocin could eliminate chemoresistant senescent cells.

ADM-resistant NKTCL cells exhibited distinct phenotypic and senescence features. LCP2 expression was significantly reduced in the plasma of R/R NKTCL patients and in chemoresistant cells, correlating inversely with the senescence marker SA-β-gal. This suggests LCP2's involvement in resistance. Moreover, LCP2 knockdown significantly enhanced chemoresistance, increased senescence-associated secretory phenotype (SASP) secretion, and promoted G0/G1 cell cycle arrest in NKTCL cells. Mechanistically, LCP2 deficiency activated the IQGAP2/LaminA/C/SUV39H1 axis, thus driving DNA damage and telomere stress-induced senescence. This also facilitated the formation of an immunosuppressive microenvironment. Importantly, targeting this axis with Epitalon and Chaetocin partially eliminated therapy-induced senescent cells, enhanced response to chemotherapeutics, and alleviated the immunosuppressive microenvironment to a certain extent in vivo. This study is the first to uncover LCP2 as a critical biomarker of senescence-related chemoresistance in NKTCL.