Abstract Immunotherapy represents a major breakthrough for multiple cancer types, yet it remains necessary to expand disease indications and improve treatment efficiency based on better understanding of tumor-immune interaction. Three currently validated biomarkers (PD-L1, MSI/dMMR and TMB) are not sufficient to predict the efficacy and patient selection for immune checkpoint therapy. We hereby propose a comprehensive tumor-immune interaction typing strategy by integrating WES, RNA-seq and TCR-seq omic technologies for the detection of gene mutations, copy number variation, fusion genes, clone variation, HLA typing, tumor antigen prediction, tumor microenvironment immune repertoire analysis and tumor lymphocyte infiltration composition under the condition of one-time sampling. Thus enabling the systematic analysis of the tumor microenvironment characteristics. Applied to a cohort of ENKTCL patients, we studied the interactions between the tumor cells and the immune system tumor microenvironment. We discovered changes of tumor immunogenicity caused by DNA variation, e.g. abnormalities in immune regulatory region 6q21, DNA repair region, cases of fusion, CNV and LOH events. These mutational events summarizes the tumor intrinsic factors in NKTL. To study the TME and “extrinsic” factors, we investigated mRNA signature enrichment patterns in patient samples and found upregulation of various immune signatures such as macrophages, T helper cells in NKT tissue samples. As examples, CD274 and PDCD1 are significantly upregulated in NKTL tissue. We also found lower TCR diversity in NKTL patients. These discoveries suggest the association of tumor microenvironment with tumor intrinsic factors to elucidate the NKTL disease etiology. Taking together, our multi-omics datasets may also provide useful resources for further interrogating with treatment and clinical outcomes. Citation Format: Yanbin Liu, Yan Gao, Yun Shao, Fang Meng, Huiqiang Huang, Frank Xiaofeng Qin. Integrated analysis for tumor-immune interaction and its application to ENKTCL immunotyping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3189.