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Dendritic cells (DCs) play a central role in the regulation of the balance between CD8 T cell immunity vs. tolerance to tumor antigens. Cross-priming, a process which DCs activate CD8 T cells by cross-presenting exogenous antigens, plays a critical role in generating anti-tumor CD8 T cell immunity. However, there are compelling evidences now that the tumor microenvironment (TME)-mediated suppression and modulation of tumor-infiltrated DCs (TIDCs) impair their function in initiating potent anti-tumor immunity and even promote tumor progression. Thus, DC-mediated cross-presentation of tumor antigens in tumor-bearing hosts often induces T cell tolerance instead of immunity. As tumor-induced immunosuppression remains one of the major hurdles for cancer immunotherapy, understanding how DCs regulate anti-tumor CD8 T cell immunity in particular within TME has been under intensive investigation. Recent reports on the Batf3-dependent type 1 conventional DCs (cDC1s) in anti-tumor immunity have greatly advanced our understanding on the interplay of DCs and CD8 T cells in the TME, highlighted by the critical role of CD103 cDC1s in the cross-priming of tumor antigen-specific CD8 T cells. In this review, we will discuss recent advances in anti-tumor CD8 T cell cross-priming by CD103 cDC1s in TME, and share perspective on future directions including therapeutic applications and memory CD8 T cell responses.

Ovarian cancer is characterized by a profoundly immunosuppressive tumor microenvironment, which has limited the clinical success of immunotherapy approaches. Antigen-based nanovaccines represent a promising strategy to enhance antitumor immunity by improving antigen delivery and immune activation. In this study, we evaluated carbon nanotubes (CNTs) bioconjugated with a peptide derived from tumor-associated antigen fucosyltransferase 4 (FUT4) as an immunomodulating platform in an immunocompetent ovarian cancer mouse model. FUT4 expression was confirmed in the ID8-Defb29/Vegf-a (ID8DVLuc) ovarian cancer model using flow cytometry and confocal microscopy. C57BL/6 mice were immunized with free peptide combined with a conventional adjuvant (PEP37 Adj), FUT4 peptide–conjugated CNTs ( f -CNTs), or f -CNTs combined with adjuvant ( f -CNTs Adj), and compared with nonimmunized controls. Immune profiling revealed increased leukocyte infiltration and enrichment of M1-like macrophages, dendritic cells, and CD8 + T cells, along with a reduction in regulatory T cells. f -CNT immunization also induced enhanced humoral responses, increased splenocyte proliferation upon ex vivo peptide restimulation, and increased ex vivo CD8 + T-cell–mediated cytotoxicity. Exploratory RNA sequencing of ascites-derived cells from f -CNT–immunized mice suggested the upregulation of genes associated with antigen processing and presentation, CD8 + T-cell activation, and Th1-type immune responses. Immunized mice exhibited reduced ascites accumulation, delayed disease progression, as assessed by bioluminescence imaging, and prolonged survival, with the most pronounced effects observed in the f -CNT group. Based on these findings, we propose that FUT4 peptide–conjugated CNTs function as an antigen-based nanoplatform that enhances antitumor immune responses in a murine ovarian cancer model. While additional studies are needed to further validate antigen specificity and therapeutic robustness, this work supports the potential of CNT-based nanocarriers as immune-modulating platforms for ovarian cancer immunotherapy.

Despite largely disappointing clinical trials of dendritic cell (DC)-based vaccines, recent studies have shown that DC-mediated cross-priming plays a critical role in generating anti-tumor CD8 T cell immunity and regulating anti-tumor efficacy of immunotherapies. These new findings thus support further development and refinement of DC-based vaccines as mono-immunotherapy or combinational immunotherapies. One exciting development is recent clinical studies with naturally circulating DCs including plasmacytoid DCs (pDCs). pDC vaccines were particularly intriguing, as pDCs are generally presumed to play a negative role in regulating T cell responses in tumors. Similarly, DC-derived exosomes (DCexos) have been heralded as cell-free therapeutic cancer vaccines that are potentially superior to DC vaccines in overcoming tumor-mediated immunosuppression, although DCexo clinical trials have not led to expected clinical outcomes. Using a pDC-targeted vaccine model, we have recently reported that pDCs required type 1 conventional DCs (cDC1s) for optimal cross-priming by transferring antigens through pDC-derived exosomes (pDCexos), which also cross-prime CD8 T cells in a bystander cDC-dependent manner. Thus, pDCexos could combine the advantages of both cDC1s and pDCs as cancer vaccines to achieve better anti-tumor efficacy. In this review, we will focus on the pDC-based cancer vaccines and discuss potential clinical application of pDCexos in cancer immunotherapy.

The success of cancer vaccines relies on the ability of dendritic cells (DCs) to efficiently prime cytotoxic CD8 T cell responses against tumors. However, in solid tumors this process is often undermined by tumor-driven immunosuppression and intrinsic defects in DC activation. Among the signaling pathways implicated in DC dysfunction, β-catenin signaling has emerged as a key regulator of immune tolerance in DCs. In parallel, inhibitory receptors such as PD-L1 and TIM-3 on DCs have been recognized as critical DC-intrinsic brakes on CD8 T cell priming and on responses to immune checkpoint blockade (ICB). Recent work has identified a DC-intrinsic immunoregulatory circuit in which β-catenin activation in DCs—particularly in cross-presenting cDC1s—induces expression of TIM-3, thereby suppressing CD8 T cell cross-priming and limiting anti-tumor CD8 T cell immunity. This β-catenin–TIM-3 axis represents a previously underappreciated layer of negative regulation that may help explain, at least in part, the limited efficacy of many current DC-based cancer vaccines. In this review, we examine how β-catenin activation in DCs, particularly in cDC1s, induces TIM-3 and related inhibitory programs that suppress cross-priming of tumor antigen-specific CD8 T cells and constrain the efficacy of DC-based vaccines. We further discuss how selectively targeting this β-catenin–TIM-3 checkpoint axis—alone or together with PD-L1 and other β-catenin–linked receptors—could restore DC function and inform rational combinations of DC-based vaccination with ICB and other T cell-based immunotherapies.

Tembusu virus (TMUV) can result in a severe disease affecting domestic ducks. The role of T cells in protection from TMUV infection and the molecular basis of T cell-mediated protection against TMUV remain largely uncharacterized. Here, we used the high-virulence TMUV strain Y and the low-virulence TMUV strain PS to investigate the protective role for TMUV-specific CD4 + and CD8 + T cells. When tested in a 5-day-old Pekin duck model, Y and PS induced comparable levels of neutralizing antibody, whereas Y elicited significantly stronger cellular immune response relative to PS. Using a duck adoptive transfer model, we showed that both CD4 + and CD8 + T cells provided significant protection from TMUV-related disease, with CD8 + T cell conferring more robust protection to recipient ducklings. For TMUV, CD4 + T cells mainly provided help for neutralizing antibody response, whereas CD8 + T cells mainly mediated viral clearance from infected tissues. The difference in T cell immunity between Y and PS was primarily attributed to CD4 + T cells; adoptive transfer of Y-specific CD4 + T cells resulted in significantly enhanced protective ability, neutralizing antibody response, and viral clearance from the brain relative to PS-specific CD4 + T cells. Further investigations with chimeric viruses, mutant viruses, and their parental viruses identified two mutations (T151A and R304M) in the envelope (E) protein that contributed significantly to TMUV-specific CD4 + T cell-mediated protective ability and neutralizing antibody response, with more beneficial effects being conferred by R304M. These data indicate T cell-mediated immunity is important for protection from disease, for viral clearance from tissues, and for the production of neutralizing antibodies, and that the difference in CD4 + T cell immunity between high- and low-virulence TMUV strains is primarily related to residues 151 and 304 in the E protein.

SARS-CoV-2-specific CD8+ T cell immunity is expected to counteract viral variants in both efficient and durable ways. We recently described a way to induce a potent SARS-CoV-2 CD8+ T immune response through the generation of engineered extracellular vesicles (EVs) emerging from muscle cells. This method relies on intramuscular injection of DNA vectors expressing different SARS-CoV-2 antigens fused at their N-terminus with the Nefmut protein, i.e., a very efficient EV-anchoring protein. However, quality, tissue distribution, and efficacy of these SARS-CoV-2-specific CD8+ T cells remained uninvestigated. To fill the gaps, antigen-specific CD8+ T lymphocytes induced by the immunization through the Nefmut-based method were characterized in terms of their polyfunctionality and localization at lung airways, i.e., the primary targets of SARS-CoV-2 infection. We found that injection of vectors expressing Nefmut/S1 and Nefmut/N generated polyfunctional CD8+ T lymphocytes in both spleens and bronchoalveolar lavage fluids (BALFs). When immunized mice were infected with 4.4 lethal doses of 50% of SARS-CoV-2, all S1-immunized mice succumbed, whereas those developing the highest percentages of N-specific CD8+ T lymphocytes resisted the lethal challenge. We also provide evidence that the N-specific immunization coupled with the development of antigen-specific CD8+ T-resident memory cells in lungs, supporting the idea that the Nefmut-based immunization can confer a long-lasting, lung-specific immune memory. In view of the limitations of current anti-SARS-CoV-2 vaccines in terms of antibody waning and efficiency against variants, our CD8+ T cell-based platform could be considered for a new combination prophylactic strategy.

HER-2/neu is the human epidermal growth factor receptor 2, which is associated with the progression of prostate cancer (PCa). HER-2/neu-specific T cell immunity has been shown to predict immunologic and clinical responses in PCa patients treated with HER-2/neu peptide vaccines. However, its prognostic role in PCa patients receiving conventional treatment is unknown, and this was addressed in this study. The densities of CD8+ T cells specific for the HER-2/neu(780–788) peptide in the peripheral blood of PCa patients under standard treatments were correlated with TGF-β/IL-8 levels and clinical outcomes. We demonstrated that PCa patients with high frequencies of HER-2/neu(780–788)-specific CD8+ T lymphocytes had better progression-free survival (PFS) as compared with PCa patients with low frequencies. Increased frequencies of HER-2/neu(780–788)-specific CD8+ T lymphocytes were also associated with lower levels of TGF-β and IL-8. Our data provide the first evidence of the predictive role of HER-2/neu-specific T cell immunity in PCa.

Tumor‐associated immunosuppressive neutrophils, termed polymorphonuclear myeloid‐derived suppressor cells (PMN‐MDSCs), compromise cancer immunotherapy. Emerging evidence indicates that neutrophil fate can be programmed as early as the hematopoietic stem and progenitor cell (HSPC) stage. Reprogramming HSPCs toward antitumor neutrophils offers a promising therapeutic strategy. Here, we demonstrate that an albumin‐bound STING agonist (Nano ZSA‐51D) reprograms HSPCs to generate antitumor neutrophils, enhancing MHC I‐mediated CD8+ T cell immunity and sensitizing tumors to α‐PD1 immunotherapy. Nano ZSA‐51D expands HSPCs and reprograms them toward granulocyte‐monocyte progenitors for neutrophil development. It further converts immature (CD101−) and mature (CD101+) neutrophils into a CD14+ICAM‐1+ subset through STING‐NF‐κB–TNF‐α signaling, enhancing tumor infiltration and antitumor activity. These neutrophils upregulate interferon signaling and MHC I antigen presentation, thereby boosting tumor‐specific CD8+ T cell responses. Notably, both adoptive transfer of Nano ZSA‐51D‐reprogrammed neutrophils and systemic Nano ZSA‐51D treatment synergizes with α‐PD1 therapy to achieve complete remission of colon tumors through neutrophil‐ and CD8+ T cell‐dependent mechanisms, with potent efficacy also validated in otherwise immune‐resistant pancreatic cancer models. Our findings establish a therapeutic strategy to reprogram HSPCs toward antitumor neutrophils, highlighting the potential of targeting early hematopoiesis to rewire neutrophil fate in cancer immunotherapy. This study demonstrates that an albumin‐bound STING agonist (Nano ZSA‐51D) reprograms HSPCs to produce antitumor neutrophils with enhanced MHC I–mediated CD8+ T cell activation, thereby sensitizing tumors to α‐PD1 therapy. These findings highlight a strategy to target early hematopoiesis for shaping neutrophil fate and potentiating cancer immunotherapy.

This study identified Faecalibaculum rodentium as a novel probiotic that suppresses colorectal cancer (CRC) via acetate, which enhances CD8 + T-cell immunity by blocking PDPN-CLEC-2 and induces tumor cell apoptosis through PI3K/AKT/mTOR pathway. These findings validated F. rodentium and acetate as dual-action therapeutic candidates through immune response activation and intrinsic tumor targeting by murine models and human CRC cell lines, thereby providing innovative strategies for CRC treatment.