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Peripheral T-cell lymphoma (PTCL) includes a varied group of post-thymic T-cell neoplasms; 40% are designated as PTCL-not otherwise specified (PTCL-NOS) due to being unclassifiable within other PTCL entities. Because of this, cases that fall into this category are heterogenous and a specific pathogenic mechanism and treatment regimen is difficult to elucidate. We identified two novel molecular subgroups. PTCL-GATA3 and PTCL-TBX21, within PTCL-NOS cases, designated with distinct T-helper transcriptional programs (TH2 and TH1, respectively). PTCL-GATA3 represents 40% of PTCL-NOS and is defined by its high expression of GATA3, the master transcriptional regulator of TH2-differentiation, and its transcriptional target genes, and its clinical aggressiveness. Analysis of candidate driver genes showed that copy number (CN) deletions in tumor protein p53 (TP53) and phosphatase and tensin homolog (PTEN), as well as mutations in TP53 and C-C Motif Chemokine Receptor 4 (CCR4), G-protein coupled receptor and GATA3 transcriptional target, with a significant number of gain-of-function mutations occurring in the cytoplasmic domain. Here, we demonstrate that each of these candidate genes play a role in TH2-like lymphomagenesis, as well as explore these two distinct subtypes further and delineate the underlying mechanisms with a multi-omics approach. We reproduced the mutational and functional signature profile of each subtype, as well as further characterized the genetic landscape through non-negative matrix factorization (NMF) clustering. Image mass cytometry (IMC) was utilized, elucidating immunosuppressive tumor microenvironment dynamics within each subtype; T-cell-mediated in PTCL-GATA3 and myeloid-mediated in PTCL-TBX21. Disruption of these candidate genes in either murine models or primary CD4+ T-cells reproduced TH2-like signatures, implicating all three in PTCL-GATA3 pathogenesis and opening more possibilities for targeted therapies. We also used surface plasmon resonance to examine the binding affinity of these mutant CCR4 proteins with their known ligands, CCL17 and CCL22, and found that the mutants had higher affinity with both ligands. This was also observed in protein-protein docking studies with an anti-CCR4 monoclonal antibody, mogamulizumab, which also identified that the most frequent mutation, CCR4Y331X, showed resistance to antibody-mediated apoptosis and had a lower affinity to the antibody. This work helps to characterize lymphomagenesis in PTCL-NOS and provides insight into therapeutic options in PTCL-GATA3.