101 Peripheral T-cell lymphoma (PTCL) represents a diverse and aggressive group of haematological malignancies, accounting for 5–10% of all non-Hodgkin’s lymphomas (NHL). Despite advances in our understanding of B-cell tumours, knowledge about T-cell leukaemias and lymphomas remains less comprehensive. A recent study sheds light on the underlying mechanisms contributing to drug resistance in PTCL, highlighting the challenges and potential therapeutic strategies to improve patient outcomes. The findings were published in the journal Molecular Cancer. PTCL encompasses approximately 30 different subtypes, as classified by the World Health Organization (WHO). These subtypes include nodal, extranodal, and leukemic PTCL, each presenting varying degrees of aggressiveness. The five-year survival rate for aggressive forms hovers around 30%, with cutaneous PTCL generally presenting a more indolent course. The study finds a number of important factors that lead to drug resistance in PTCL. These include the heterogeneity of the tumour, the tumour microenvironment (TME), and signalling pathways that do not work right. Tumour heterogeneity. PTCL’s remarkable heterogeneity stems from the absence of distinct molecular markers and morphological features. This variety makes it harder to find treatments that work for everyone, since different types of PTCL have different ways of fighting off treatments. Tumour microenvironment (TME). The TME plays a crucial role in the progression and resistance of PTCL. It comprises tumour cells, immune cells, stromal cells, blood vessels, and the extracellular matrix. Treatment resistance is caused by things that happen in the TME, like the release of soluble factors and the interaction between stroma cells and tumour cells. The study emphasises the need for a deeper understanding of the PTCL TME, drawing comparisons from more extensively studied B-cell NHL environments. Signalling pathways. Genetic analyses have unveiled critical insights into the signalling pathways involved in PTCL pathogenesis. Key pathways include NF-κB, Notch, JAK/STAT3, RHOA, and PI3K/AKT. Mutations and aberrant activation within these pathways lead to uncontrolled cell proliferation and survival, contributing to intrinsic and acquired drug resistance. Existing treatments for relapsed or refractory PTCL (R/R PTCL) face significant obstacles due to the aforementioned resistance mechanisms. Chemotherapy treatments like CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) are not as good at killing PTCL as they are at killing B-cell lymphomas. Approximately 70% of PTCL patients develop relapsed or refractory disease following first-line therapy, underscoring the urgent need for more effective treatment strategies. Targeted therapies. Advances in understanding PTCL biology have driven the development of targeted therapies. For instance, CD30 monoclonal antibody agents, such as Brentuximab Vedotin (BV), have shown promise in treating CD30-positive PTCL. BV’s efficacy has been demonstrated in both combination therapies and as monotherapy for relapsed and refractory cases. Epigenetic modulators. Epigenetic alterations play a significant role in PTCL resistance. Histone deacetylase (HDAC) inhibitors, like romidepsin and belinostat, have been shown to be effective against lymphoma. But resistance to HDAC inhibitors remains a challenge, necessitating further research into combination therapies to enhance their effectiveness. PI3K/Akt/mTOR pathway onhibitors. Inhibiting the PI3K/Akt/mTOR pathway presents another promising approach. Duvelisib, an oral inhibitor of PI3Kδ and PI3Kγ, has shown efficacy in clinical trials involving R/R PTCL patients. Similarly, ongoing investigations into copanlisib and Aurora A kinase inhibitors highlight the potential for these agents to improve treatment outcomes. PD-1/PD-L1 inhibitors. The PD-1/PD-L1 pathway is a key regulator of immune evasion in tumours. Blocking this pathway with inhibitors has emerged as a viable strategy for treating various cancers, including PTCL. Clinical trials exploring the efficacy of PD-1/PD-L1 inhibitors are underway, offering hope for new therapeutic options. The study underscores the complexity of PTCL and the multifaceted nature of drug resistance. It highlights the importance of a comprehensive understanding of tumour biology and the TME to develop more effective therapies. PTCL patients may have a better outlook if targeted therapies, epigenetic modulators, and pathway inhibitors are used in ongoing research and clinical trials.