Colsen

Theranostics. 2026 Mar 17;16(10):5393-5405. doi: 10.7150/thno.128187. eCollection 2026.

ABSTRACT

RATIONALE: Short major histocompatibility class I epitopes can be coupled to the surface of immunogenic liposomes to elicit antigen-specific CD8⁺ T cells with vaccination. Here, we examined whether the co-incorporation of GM3 ganglioside, a lipid which targets CD169, a sialic acid-binding receptor, would further improve the immunogenicity of this approach.

METHODS: Liposomes were formed with GM3 incorporated and were assessed for CD169 targeting and anti-tumor immunogenicity in murine models. Antigen-specific CD8⁺ T cell populations and characteristics were investigated to examine the effect of liposome formulations.

RESULTS: GM3 was readily incorporated into immunogenic liposomes and did not interfere with the particle formation with a recently discovered murine renal carcinoma MHC-I neoepitope, Nes2LR. GM3 enhanced the CD169 targeting of liposomes. Immunization with liposomal particles that included GM3 improved antigen-specific CD8⁺ T cell responses for not only the Nes2LR neoepitope, but for other tumor-associated short MHC-I murine tumor epitopes or mimotopes, including E7_49-57, and the gp70 mimotope AH1-A5. Immunization of the E7 epitope with GM3 particles induced high-frequency E7-specific CD8⁺ T cells and effectively reversed the tumor growth of large, established TC-1 tumors as an immune monotherapy. Immunization of the Nes2LR neoepitope in GM3 particles led to delayed tumor growth of RENCA tumors.

CONCLUSION: GM3 ganglioside-containing liposomes that display short peptide epitopes and incorporate immunological adjuvants can be used to elicit potent anti-tumor responses in murine models. Further research is required to further assess the translational potential of this approach.

PMID:41993615 | PMC:PMC13080682 | DOI:10.7150/thno.128187

Biology (Basel). 2026 Mar 27;15(7):538. doi: 10.3390/biology15070538.

ABSTRACT

Cancer immunotherapy has transformed the clinical management of several malignancies; however, its efficacy remains limited in tumors with low mutational burden and restricted availability of classical mutation-derived neoantigens. In this context, increasing evidence indicates that the tumor immunopeptidome extends far beyond canonical protein-coding regions, incorporating peptides derived from non-coding transcripts through non-canonical translation mechanisms. Long non-coding RNAs (lncRNAs), traditionally regarded as transcriptional or post-transcriptional regulators, have recently emerged as an unexpected source of small open reading frame-encoded peptides (lncPEPs). A subset of these peptides is processed and presented by major histocompatibility complex class I molecules, generating tumor-specific neoantigens capable of eliciting CD8⁺ T cell responses. Owing to the high tissue and context specificity of lncRNA expression, lncRNA-derived neoantigens offer unique advantages over mutation-based targets, including increased tumor selectivity and potential recurrence across patient subsets. In this review, we synthesize current knowledge on the biogenesis, detection, and immunogenic potential of lncRNA-derived peptides, highlighting experimental and computational strategies for their identification within the cancer immunopeptidome. We discuss the challenges associated with their validation and clinical translation, as well as their relevance for the development of vaccines and adoptive T cell-based therapies. Finally, we illustrate these concepts using epithelial ovarian cancer as a representative model of low-mutational-burden tumors, where lncRNA-derived neoantigens may help overcome current limitations of immunotherapy and enable patient stratification for personalized treatment approaches.

PMID:41972540 | PMC:PMC13072341 | DOI:10.3390/biology15070538

Immunity. 2026 Apr 8:S1074-7613(26)00075-0. doi: 10.1016/j.immuni.2026.02.005. Online ahead of print.

ABSTRACT

DNA mutations are a well-characterized source of neoepitopes in immunotherapy. Here, we examined the contribution of dysregulated RNA processing to neoantigen production. Leveraging multi-omics and checkpoint inhibitor (CPI) response data from >1,000 patients, we identified reduced activity of the nonsense-mediated mRNA decay (NMD) pathway kinase SMG1 as a predictor of improved CPI response. NMD inhibition through SMG1 targeting stabilized transcripts containing premature termination codons, most of which were of non-mutational origin. This reshaped the major histocompatibility complex class I (MHC class I)-bound immunopeptidome and increased neoantigen abundance to levels comparable to high mutation burden tumors. Functionally, NMD inhibition drove antigen-dependent T cell-mediated tumor cell killing in vitro, promoted activation of tissue-resident T cells in patient-derived models ex vivo, and improved CPI efficacy in vivo. Our findings establish NMD inhibition as a strategy to harness a previously inaccessible source of canonical and non-canonical neoantigens, with the potential to increase tumor immunogenicity across cancers.

PMID:41956098 | DOI:10.1016/j.immuni.2026.02.005

Biomaterials. 2026 Mar 14;333:124128. doi: 10.1016/j.biomaterials.2026.124128. Online ahead of print.

ABSTRACT

Nanoparticle (NP)-based cancer vaccine therapies conventionally incorporate tumor-associated antigens or neoantigens that are major histocompatibility complex (MHC) class I-restricted, an approach that educates cytotoxic CD8⁺ T cells to respond to tumors. Helper CD4⁺ T cells can support CD8⁺ T cell-mediated responses and are activated by MHC class II-presented peptides. However, strategies to deliver MHC class I and II antigens using NPs as vehicles have not been systematically examined for anti-cancer immunity. In melanoma and colon carcinoma murine models, we evaluated the effects of transporting MHC class I and class II antigens using different NP-based approaches, with the NPs being within the optimal size range for uptake by antigen-presenting dendritic cells. We found that co-delivering MHC class I and II peptides on dual-antigen NPs increased proliferation of cytotoxic and helper T cells relative to single-antigen NPs alone (i.e., either MHC class I or II peptide on a NP) and to mixtures of the single-antigen NPs. For both tumor models, dual-antigen NPs also elicited higher antigen-specific Th1 responses, including up to 8-fold higher interferon (IFN)-γ secretion. Significantly, immunization with the dual-antigen NPs prolonged survival, with 40% of melanoma- and 71% of colon carcinoma-bearing mice surviving, compared to 0% and 13%, respectively, of those treated with component- and dose-equivalent mixtures of single-antigen NPs. This highlights the importance of the antigen delivery strategy and locale with respect to the NP, with the simultaneous co-delivery of both MHC class I and II antigens on the same NP being critical for anti-tumor potency.

PMID:41946315 | DOI:10.1016/j.biomaterials.2026.124128