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Immuno-oncology holds promise for transforming patient care having achieved durable clinical response rates across a variety of advanced and metastatic cancers. Despite these achievements, only a minority of patients respond to immunotherapy, underscoring the importance of elucidating molecular mechanisms responsible for response and resistance to inform the development and selection of treatments. Breakthroughs in molecular sequencing technologies have led to the generation of an immense amount of genomic and transcriptomic sequencing data that can be mined to uncover complex tumor-immune interactions using computational tools. In this review, we discuss existing and emerging computational methods that contextualize the composition and functional state of the tumor microenvironment, infer the reactivity and clonal dynamics from reconstructed immune cell receptor repertoires, and predict the antigenic landscape for immune cell recognition. We further describe the advantage of multi-omics analyses for capturing multidimensional relationships and artificial intelligence techniques for integrating omics data with histopathological and radiological images to encapsulate patterns of treatment response and tumor-immune biology. Finally, we discuss key challenges impeding their widespread use and clinical application and conclude with future perspectives. We are hopeful that this review will both serve as a guide for prospective researchers seeking to use existing tools for scientific discoveries and inspire the optimization or development of novel tools to enhance precision, ultimately expediting advancements in immunotherapy that improve patient survival and quality of life., Competing Interests: Competing interests: CAR and KM declare no conflicts of interest. EMVA disclosures: Advisory/consulting: Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics, Serinus Bio. Research support: Novartis, Bristol-Myers Squibb, Sanofi. Equity: Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics, Serinus Bio. Travel reimbursement: None. Patents: Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)