Editorial: Understanding the Interplay Between Tumor Immune Microenvironment and Neoantigens for Improved Immunotherapy

Sheefa Mirza^1*Clem Penny¹Aijaz Ahmad²

• ¹Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa
• ²Division of Pulmonary, Allery and Critical Care Medicine, Stanford University, USA, Stanford, United States

The rise of cancer immunotherapy has transformed oncology, yet its success remains limited by tumor immune escape, intratumoral heterogeneity, and insufficient neoantigen targeting. Central to immunotherapy's success are tumor neoantigens - novel peptides arising from tumor-specific mutations - that have the capacity to elicit potent anti-tumor immune responses. However, the tumor immune microenvironment (TIME) frequently imposes complex regulatory networks and immunosuppressive obstacles that limit therapeutic efficacy. Although neoantigen-based approaches herald the promise of personalized and effective treatments, the complex and often suppressive TIME remain a formidable barrier to their full clinical success. Thus, understanding the complex relationships between TIME and neoantigens is essential for designing more effective, personalized immunotherapies. This Research Topic "Understanding the Interplay Between Tumor Immune Microenvironment and Neoantigens for Improved Immunotherapy" aggregates cutting-edge studies elucidating the complex interactions between tumor cells, immune components, and neoantigen landscapes that modulate tumor progression and response to immunotherapy. The collective insights offered by these contributions not only deepen our mechanistic understanding but also pave the way for novel biomarker development and innovative therapeutic strategies. A central theme across these contributions is the understanding that TIME is a dynamic ecosystem shaped by genetic, epigenetic, and environmental signals. The identification and functional characterization of neoantigens provide a crucial entry point into this complexity, as they not only serve as markers of tumor heterogeneity but also act as direct targets for T cell - mediated therapy. Hu et al. explores the biology, prediction, and therapeutic potential of neoantigens - tumor-specific peptides arising from somatic mutations - and their role in personalized cancer immunotherapy. The authors describe the mechanisms underlying neoantigen generation and T cell recognition via MHC presentation, assess current methods for neoantigen screening (including DNA/RNA sequencing, mass spectrometry, machine learning-based tools, and molecular docking), and highlight the limitations, such as false positives, incomplete transcript coverage, and lack of high-resolution peptide structures. They also outline potential solutions integrating multi-omics, improving prediction algorithms, and advancing proteomic validation; and argue that refined neoantigen identification methods are essential for enhancing vaccine efficacy and shaping the future of cancer immunotherapies. Complementing this focus on neoantigen biology, Han et al. analyzes over 2,100 publications from 2003–2023. The study identifies immune cell dynamics - particularly CD8+ T cells, regulatory T cells, tumor-associated macrophages - as well as cancer-associated fibroblasts, extracellular matrix remodeling, and immunotherapy as major research hotspots. More recent themes such as ferroptosis, biomarker discovery, diagnostic signatures, and TME heterogeneity are highlighted as growing areas of interest. The authors conclude that advancing these emerging directions, particularly by integrating ferroptosis research with biomarker development and improved characterization of TME complexity, will be essential to improving HCC management and therapeutic strategies. In parallel, review by Liu et al. offers a detailed overview of the immune cell populations activated by neoantigen-based cancer vaccines, emphasizing how different immune cells interact within the TIME to generate antitumor responses. It discusses how transcriptomic profiling and advances in single-cell sequencing have revealed phenotypic signatures in neoantigen-specific T cells, which correlate with vaccine efficacy. The review concludes that improving clinical outcomes will depend on deeper characterization of these immune cell types, optimizing vaccine design and delivery, and strategically combining neoantigen vaccines with therapies that modulate immunosuppression in the TIME. Additionally, Chen et al. reported how extracellular matrix stiffness, abnormal vasculature, and high interstitial pressure hinder TIL infiltration in tumors. It highlights key molecular pathways driving these barriers and outlines strategies - such as LOX and YAP/TAZ inhibitors, hyaluronidase treatment, and vascular normalization - to enhance lymphocyte entry and boost the efficacy of neoantigen-based therapies. The dynamic interplay between therapy and the TIME is further explored by Xu et al., who comprehensively examines the interplay between radiotherapy (RT) and the TIME in pancreatic ductal adenocarcinoma (PDAC). It highlights RT's ability to induce immunogenic cell death, enhance antigen presentation, modulate cytokine profiles, and upregulate immune checkpoint molecules, potentially transforming immunologically "cold" tumors into "hot" ones. However, the dense stroma and immunosuppressive cells in PDAC limit immune activation and therapy effectiveness. The review emphasizes the promise of combining RT with immunotherapy and the use of advanced single-cell and spatial transcriptomic technologies to better understand the TME and personalize treatment strategies for improved outcomes in this challenging cancer. Building on these mechanistic insights, Zhang et al. presents a phase II randomized trial protocol testing the combination of personalized neoantigen peptide vaccines with precision critical lesion radiotherapy (CLERT) in advanced solid tumors. The study aims to overcome the limitations of neoantigen vaccines in late-stage patients by synergistically enhancing immune activation via targeted radiation to key tumor areas. It uses a 1:1 randomized, open-label, multicenter design including a crossover option from placebo to vaccine upon progression. The trial assesses progression-free survival and response rates across diverse cancers, leveraging shared neoantigens for broader applicability. This innovative approach integrates precision radiotherapy and neoantigen vaccination, offering a promising platform for advancing combination immunotherapies in challenging advanced cancers. Together, these studies illustrate how dissecting the reciprocal interactions between neoantigens and the immune microenvironment can accelerate the next generation of precision immunotherapies. They highlight the importance of integrating high-resolution mapping of TIME components, advanced computational algorithms for neoantigen prioritization, and rationally designed combination therapies. By linking mechanistic insights with translational strategies, this Research Topic advances our understanding of how tumors evolve under immune pressure and how neoantigen-based interventions can be optimized for clinical benefit. In conclusion, the contributions gathered here not only expand our knowledge of TIME– neoantigen interactions but also provide a roadmap for developing more effective and durable cancer immunotherapies. We anticipate that these insights will inspire continued interdisciplinary research, ultimately enhancing the precision and efficacy of immunotherapeutic strategies for cancer patients worldwide.