P1, N=24, Active, not recruiting, University of Utah | Suspended --> Active, not recruiting

P1/2, N=16, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=60 --> 16

P1, N=15, Active, not recruiting, Weill Medical College of Cornell University | Recruiting --> Active, not recruiting | Trial primary completion date: Sep 2026 --> May 2026

MHC Class II blockade lowered the ability of bone marrow to boost tumor growth, and reduced the ability of valemetostat with anti-PD1 to reduce tumoroid growth. Patient samples revealed a strong negative correlation between EZH2 and MHC Class II, suggesting that targeting EZH2 activity could lead to marked increase in MHC Class II and improve treatment responses in lung squamous cell carcinomas.

P1/2, N=46, Not yet recruiting, The First Affiliated Hospital with Nanjing Medical University

P1/2, N=30, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Jun 2027 | Trial primary completion date: Jun 2026 --> Jun 2027

P3, N=180, Not yet recruiting, Tarapeutics Science Inc.

P2, N=80, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

P2, N=10, Active, not recruiting, University of Florida | Trial completion date: Apr 2026 --> Dec 2026

DOX-resistant breast cancer cell models were established and treated with the EZH2 inhibitors tazemetostat or GSK126, alone or in combination with DOX. EZH2 is a critical determinant of DOX resistance in breast cancer by sustaining DNA damage tolerance and metabolic homeostasis. Pharmacological targeting of EZH2 in combination with DOX represents a rational strategy to overcome chemoresistance in breast cancer.

Pharmacological inhibitors of EZH2, including tazemetostat, have shown promise in preclinical melanoma models by restoring antigen presentation, enhancing CD8+ T-cell infiltration, and reversing transcriptional programs associated with immune resistance. This review aims to summarize the role of EZH2 in the molecular pathogenesis of ALM, emphasizing its contributions to epigenetic regulation, tumor plasticity, and immune escape, and discusses emerging therapeutic strategies targeting EZH2-mediated pathways to improve outcomes for this aggressive melanoma subtype.

Notably, TZM monotherapy inhibited tumor growth in both FN- and FP-RMSCRR xenografts, uncovering a therapy-induced vulnerability. Our integrative multi-omics analysis reveals EZH2-dependent molecular programs underpinning radioresistance and supports EZH2 targeting as a rational radiosensitizing and therapeutic strategy in RMS, including recurrent and RT-refractory disease.