Innovative conventional and non-conventional target antigens to improve cancer immunotherapy

Cancer immunotherapy stands at the forefront of oncology by mobilizing the immune system to identify and destroy malignant cells. While existing therapies targeting a narrow spectrum of conventional antigens, primarily tumor-associated antigens and selected neoantigens, have achieved significant breakthroughs, they are hampered by several inherent limitations. Key challenges include the selection and validation of highly immunogenic antigens, tumor heterogeneity, antigen loss variants, immune escape mechanisms, and adverse effects stemming from the overlap between tumor and normal tissue antigen profiles. These obstacles contribute to limited applicability, suboptimal response rates, therapy resistance, and hindered long-term benefit for many patients. Recent developments in high-throughput genomic, proteomic, immunopeptidomic, and single-cell analyses have revolutionized our understanding of the tumor antigenic repertoire. Beyond classical surface proteins and commonly studied neoantigens, an array of non-conventional, “cryptic” antigens has been identified. These include antigens arising from alternative mRNA splicing, non-coding genomic regions, endogenous retroviruses, gene fusions, and diverse post-translational modifications, as well as those influenced by the tumor microenvironment and associated microbiota. Emerging evidence highlights the potential of these non-traditional targets to improve tumor specificity, reduce immune escape, and address patient-to-patient variability. Nevertheless, the translation of these findings into clinically effective immunotherapies remains in its infancy, with critical questions regarding the identification, optimal selection, validation, and application of these promising antigens largely unresolved.This Research Topic aims to advance the field of cancer immunotherapy by exploring and defining innovative approaches that leverage both conventional and non-conventional target antigens. The primary objectives are to systematically assess the advantages and limitations of diverse antigen types, establish robust criteria for their prioritization based on specificity, immunogenicity, sharing among patients and clinical feasibility, and to foster strategies for their successful integration into existing and novel immunotherapeutic modalities. This will facilitate the rational design of therapies that are safer, more effective, and broadly applicable across varied malignancies.The scope of this Research Topic encompasses foundational, translational, and clinical studies that interrogate the landscape of target antigens relevant to cancer immunotherapy, while recognizing potential limitations in experimental models and clinical validation. To gather further insights into the current and emerging opportunities in this area, we welcome articles addressing, but not limited to, the following themes:• Comprehensive profiling and critical re-evaluation of conventional tumor-associated and neoantigens.• Identification and functional characterization of non-conventional antigens (e.g., those derived from alternative splicing, gene fusions, post-translational modifications, microbiome, etc.)• Methods and criteria for prioritizing antigen targets suitable for clinical translation.• Integration of novel antigens into next-generation immunotherapy platforms (e.g., CAR-T, TCR-modified cells, bispecific antibodies, and cancer vaccines).• Strategies to mitigate toxicity, overcome immune escape, and enhance durability and breadth of response.• Preclinical models, biomarker development, immunomonitoring approaches, safety assessments, and translational hurdles in targeting innovative antigens.We invite the submission of original research articles, reviews, perspectives, and technical advances that align with these themes and contribute to the next generation of cancer immunotherapy innovation. Topic editors: Riccardo Dolcetti, Ileana Mauldin, Yang Zeng Source: https://www.frontiersin.org/research-topics/82951/innovative-conventional-and-non-conventional-target-antigens-to-improve-cancer-immunotherapy