Introduction

Cancer immunotherapy has shifted the paradigm for cancer treatment over the past few decades, especially with the success of immune checkpoint blockade and chimeric antigen receptor (CAR) T-cell therapy1. Cancer vaccines that aim to modulate antigen-presenting cells (e.g., dendritic cells (DCs)) with tumor antigens and adjuvants, with the goal of eliciting potent and persistent tumor-specific cytotoxic T lymphocyte (CTL) responses, have also achieved significant progress2,3. DCs are the prominent type of antigen-presenting cells in the body and serve as conduits for communication within the immune system, as reflected by their roles as sentinels to capture and process antigens from the surrounding environment. Upon encountering antigens, DCs process and present the antigens and migrate to lymphatic tissues, where they present the antigens to T and B cells, thereby driving the clonal expansion of antigen-specific T and B cells for the orchestration of adaptive immune responses4. DCs should be capable of efficiently presenting antigens via major histocompatibility complexes (MHCs), expressing sufficient costimulatory signals on the cell membrane, exhibiting a phenotype with superior migratory and tissue penetration properties, and releasing immunomodulatory molecules to further modulate the proliferation and function of T and B cells and enable the optimal priming of antigen-specific T and B cells5. However, DCs are often heterogeneous and have multifaceted functions in immunomodulation by priming and regulating the activation, differentiation, and function of tumor antigen-specific CTLs, CD4+ T helper cells, regulatory T cells, and B cells6,7. In addition to tumor antigens and adjuvants, additional immunomodulatory signals are often needed to control the T- and B-cell priming functions of DCs8,9.

Cytokines play critical roles in maintaining the survival and proliferation of immune cells, controlling the differentiation process and phenotypes of immune cells, and orchestrating interactions between different types of immune cells10,11,12. For example, IL-2, IL-12, and IL-15 are able to drive the proliferation of effector CD8+ and CD4+ T cells in peripheral lymphoid tissues and the tumor microenvironment, thus amplifying the overall CTL response and antitumor efficacy13,14. Granulocyte‒macrophage colony-stimulating factor (GM-CSF) can induce the differentiation and proliferation of DCs15. Certain cytokines, such as interferons and TGF-β, can also directly affect the survival and growth of tumor cells (Fig. 1)16,17,18. In clinical settings, cytokine therapy has been actively evaluated for treating various types of cancer. To date, IL-2 has been approved by the FDA as a treatment for advanced renal cell carcinoma and metastatic melanoma, and IFN-α has been approved as a treatment for hairy cell leukemia, follicular non-Hodgkin lymphoma, melanoma and AIDS-related Kaposi’s sarcoma19,20,21. However, the short half-life, low patient response rate, and severe side effects of proinflammatory cytokines have limited their utility for cancer treatment22. In particular, the systemic administration of cytokines often causes system-level inflammation and off-target side effects, resulting in the failure of most cytokine therapies in clinical trials23. These issues have motivated the development of new strategies that enable the controllable exposure of cytokines to immune cells of interest. For example, the controlled expression of cytokines in DCs holds great promise for precisely orchestrating T- and B-cell priming processes, potentially achieving increased antitumor efficacy with reduced side effects24.

Fig. 1: Functions of proinflammatory cytokines in the tumor microenvironment.
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Schematic illustration of the major immune cells and representative proinflammatory cytokines found in the tumor microenvironment. Proinflammatory cytokines can regulate tumor growth, the proliferation of dendritic cells, and the cytotoxic activities of lymphocytes and myeloid cells to increase antitumor efficacy.

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Upregulating the expression of cytokines in DCs is promising for finely tuning adaptive immune responses and the overall therapeutic efficacy of immunotherapies against malignant cancers24. Adjuvants or other molecules that can bind to Toll-like receptors (TLRs) on the membrane of DCs can often stimulate the intracellular pathways associated with cytokine expression and have been widely incorporated into the design of vaccines and other immunotherapies. These efforts have been reviewed by others25,26,27 and will not be the focus of this review. Genetic engineering of DCs with cytokine-encoding plasmids has been actively explored to directly control the expression levels of specific cytokines. The engineered DCs overexpress specific cytokines either intracellularly or on the cell membrane. For the former, cytokines either drive the activation and proliferation of DCs themselves or are gradually released to modulate the extracellular environment28. For the latter, cytokines are displayed on the surface of DCs to orchestrate intercellular interactions with other immune cells, such as CD8+ T cells29,30. In addition to genetic engineering methods, physical adsorption or chemical conjugation of cytokines to the membrane of DCs has also been attempted to provide a continuous activation signal to the interacting cells (e.g., T cells)31. This review provides a brief overview of strategies that have been utilized to upregulate the expression of cytokines in DCs or surface display of cytokines on DC membranes and their applications for the development of improved cancer immunotherapies. We discuss the current research progress in preclinical and clinical settings, potential challenges for each strategy, and future directions for the development of cytokine expression or display approaches.

Cytokine therapy in the clinic

Over the past few decades, various types of proinflammatory cytokines have been evaluated for cancer treatment in clinical trials, many of which have shown CTL responses and antitumor efficacy against blood and solid tumors at different stages of cancer (Table 1). Among them, IFN-α and IL-2 have been approved by the FDA, and several other proinflammatory cytokines are actively being explored in numerous ongoing clinical trials32. In 1986, IFN-α became the first FDA-approved cytokine to treat human cancer, particularly hairy cell leukemia33. Since then, IFN-α has been extensively tested as a treatment for various types of hematological malignancies and solid tumors34. To date, IFN-α has obtained FDA approval as a primary treatment for individuals with metastatic renal cell carcinoma, AIDS-related Kaposi’s sarcoma, follicular lymphoma, chronic myelogenous leukemia, hairy cell leukemia, and cervical intraperitoneal neoplasms and as an adjuvant therapy for patients with completely resected stage III or IV melanoma22,23. Nevertheless, the utilization of IFN-α as an anticancer therapy is not without challenges, as it exhibits significant dose-dependent toxicity and often causes symptoms, including fever, fatigue, headache, and gastrointestinal disturbances35. Additionally, neuropsychiatric manifestations, such as depression, confusion, and mania, coupled with electroencephalographic alterations, have been documented, and instances of suicide have been associated with IFN-α use35.

Table 1 Representative cytokine therapies investigated in clinical trials.
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IL-2 received FDA approval for treating metastatic renal cell carcinoma in 1992 and metastatic melanoma in 199336. IL-2 plays an important role in regulating both the adaptive and innate immune systems. By functioning as a T-cell-stimulating agent during the initiation of immune responses, IL-2 can facilitate the activation and proliferation of antigen-specific CD8+ T cells, effector CD4+ T cells, and natural killer (NK) cells37. Over the past few decades, IL-2 treatment has been scrutinized across various dose ranges, schedules, and administration routes in the pursuit of maximizing efficacy while minimizing toxicity38. Due to the short blood half-life and poor pharmacokinetics of IL-2 and the imperative to achieve a potent immunomodulatory effect, a high dose of IL-2 is often needed, inevitably causing severe systemic toxicity, including vascular leak syndrome, pulmonary edema, hypotension, acute renal insufficiency, and, rarely, myocarditis39.

Other interleukin family cytokines have also been actively explored in clinical trials. IL-15 was shown to improve the proliferation and cytotoxic function of CD8+ T cells and NK cells and thus lead to an enhanced CTL response and therapeutic efficacy40. Despite its therapeutic potential, over 170 global clinical trials involving IL-15 for cancer treatment have been frequently limited by adverse effects, including bleeding, papilledema, uveitis, pneumonitis, duodenal erosions, and fatalities41. Similarly, clinical trials involving IL-7, IL-12, and IL-21 have documented side effects such as fatigue, dyspnea, acidosis, leukopenia, elevated liver function, and even death42,43,44. While these cytokine therapies show promise in eliciting a robust CTL response against different types of blood and solid tumors, the associated adverse effects necessitate the development of strategies for the controlled exposure of proinflammatory cytokines to immune cells.

Intrinsic cytokines in DCs

DCs can intrinsically express various types of cytokines that either drive self-proliferation and differentiation or modulate interacting lymphocytes and other immune cells45. For example, DCs express GM-CSF, which can maintain the survival and proliferation of DCs and eosinophils46. During the CD8+ T-cell priming process, DCs express and release IFN-γ and IL-12 to promote the activation and maturation of CD8+ T cells, which is critical for generating robust CTL responses and antitumor efficacy. DCs can also express transforming growth factor-β (TGF-β), IL-10, and IL-1β to regulate the differentiation of CD4+ T cells and modulate T helper 1 and 2 responses47,48,49. In addition to T cells, DCs also express and release various types of cytokines, including IL-10, TGF-β, IL-21, IL-4, and IL-9, to modulate the differentiation and function of B cells and orchestrate antigen-specific humoral responses50. DCs also play a crucial role in mediating innate immune responses. One notable example is the ability of DCs to modulate the function of NK cells via the release of cytokines such as IL-12, IL-15, IL-18, and type I interferons51. DCs can also express and release IL-3 and IL-4 to regulate the recruitment and differentiation of neutrophils and basophils and IL-3, IL-4, IL-5, and GM-CSF to modulate eosinophils (Fig. 2)52,53. However, the level of cytokines intrinsically expressed and released by DCs is often low, depending on the status of inflammation and the type of tissue microenvironment54,55,56. Additionally, the mix of proinflammatory and anti-inflammatory cytokines released by DCs makes a predicting the overall immunomodulatory effects difficult57. These issues have motivated the development of new strategies to upregulate the expression of specific cytokines in DCs and improve the precise priming of antigen-specific T and B cells and other immune cells.

Fig. 2: Dendritic cells express various types of cytokines to modulate interacting or surrounding immune cells.
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DCs express a wide spectrum of interleukins (IL-12, IL-15, IL-18, IL-10, IL-21, IL-4, IL-9, IL-1β, IL-3, and IL-5), type I interferons, transforming growth factor β, and chemokines (GM-CSF) to stimulate or suppress interacting or surrounding T cells, B cells, NK cells, neutrophils, eosinophils, and basophils.

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Overexpression of soluble cytokines in DCs

DC-mediated priming of antigen-specific T cells is a crucial step in adaptive immunity. For a desirable priming process, T cells need three signals: MHC–antigen complexes presented by DCs, costimulatory signals from the DC membrane, and soluble cytokines (e.g., IL-2) that can maintain the survival and proliferation of T cells58. These processes often require the presence of DCs with the right phenotype, proper activation status, and high antigen presentation efficiency, as well as the exposure of a sufficient amount of cytokines to T cells. The incorporation of an adjuvant that can activate DCs and facilitate antigen delivery into DCs are common strategies to improve the activation status and antigen presentation efficiency of DCs, but additional cytokines are often needed to maintain the survival and proliferation of DCs and T cells59. For example, exogenous GM-CSF can be added to facilitate the proliferation and maturation of DCs60. Exogenous IL-2 and IL-15 are also commonly used to increase the expansion of T cells61. However, while the simple addition of soluble cytokines to DC–T-cell cocultures may improve the expansion of DCs or T cells, the seamless integration of cytokine-mediated cell modulation and DC-mediated T-cell priming processes remains a significant challenge. To this end, the overexpression of cytokines in DCs via genetic methods has been actively pursued as a means to better orchestrate DC-mediated T-cell priming processes (Fig. 3)62. For example, GM-CSF-overexpressing DCs could exhibit enhanced survival, persistence, and activation for the improved priming and expansion of T cells63,64. IL-2-overexpressing DCs can simultaneously prime antigen-specific T cells and gradually release IL-2 to drive the expansion of primed T cells65.

Fig. 3: The overexpression of cytokines in DCs via viral transduction orchestrates T-cell priming processes.
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Cytokine-encoding DNA is delivered to DCs via viral vectors and becomes integrated into the genome of host DCs for subsequent transcription and translation into cytokines. The cytokines expressed by DCs could facilitate the priming process of T cells. During T-cell priming, (a) stimulatory signals (MHCI-Ag-TCR), (b) costimulatory signals (CD80-CD28), and (c) DC-released cytokines collectively contribute to the expansion of antigen-specific T cells.

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Overexpression of soluble DC-effector cytokines

The ability of DCs to present antigens, express costimulatory signals, and prime T and B cells is intrinsically heterogeneous. DCs also have a relatively short lifespan (up to two weeks)66. These characteristics pose significant challenges for properly equipping DCs for the T- and B-cell priming processes. One common approach is to treat DCs with GM-CSF or M-CSF, which has long been used to differentiate DCs from bone marrow precursor cells and maintain the survival and proliferation of DCs. Indeed, Sipuleucel-T (Provenge), the first FDA-approved therapeutic cancer vaccine, utilizes the treatment of monocyte-derived DCs with a fusion protein of GM-CSF and prostatic acid phosphatase (PAP) antigen67. Upon infusion into patients, the engineered DCs are expected to exhibit improved survival and activation, an enhanced antigen-specific CTL response, and improved antitumor efficacy. Approaches based on various materials, including the use of nanoparticles, microparticles, polymer conjugates, and polymeric gels, have also been explored for the controlled exposure of immunomodulatory cytokines (e.g., GM-CSF) to DCs (Fig. 4a)68. Immature DCs can also be recruited to GM-CSF-releasing macroporous materials such as alginate hydrogels and mesoporous silica rods, where they can be modulated by cytokines and adjuvants in situ (Fig. 4b)69,70. DCs have been virally transduced with GM-CSF to enable stable expression. These transduced DCs can consistently express GM-CSF to drive self-proliferation and activation and show an improved ability to present tumor antigens and prime antigen-specific T and B cells63,64. In addition to GM-CSF, the overexpression of Fms-like tyrosine kinase 3 (Flt3) ligands in DCs via viral transduction methods has also been actively explored to enrich the population of type 1 conventional DCs (cDC1s), a subtype of DCs with superior antigen cross-presentation and priming of effector CD8+ T cells. Compared with the administration of unmodified DCs, the administration of Flt3 ligand-overexpressing DCs into tumor-bearing mice resulted in significantly greater numbers of cDC1s in the tumor microenvironment28.

Fig. 4: Material-based approaches to control the exposure of DCs to cytokines.
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a Schematic illustration of various material approaches used to deliver immunomodulatory cytokines. Adapted from Pires et al.68. b Macroporous hydrogels loaded with chemokines (e.g., GM-CSF) for in situ DC recruitment and modulation. Adapted from Wang et al.70.

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Overexpression of cytokines that affect neighboring T and B cells

In addition to overexpressing cytokines that can maintain the proliferation and activation of DCs, genetic engineering of DCs to overexpress proinflammatory cytokines that can drive the proliferation and maturation of T and B cells has also been actively explored (Fig. 5a). In these designs, cytokines are expressed in DCs and then are gradually released from DCs to modulate neighboring immune cells, such as T cells and B cells (Fig. 5b). For example, DCs transduced with IL-2 or IL-15 were shown to result in improved expansion of antigen-specific CD8+ T cells and to elicit a stronger CTL response and antitumor efficacy71,72,73. IL-12-transduced DCs were also shown to enrich CD8+ T cells in the tumor microenvironment compared with nontransduced DCs74. In addition to T helper 1 (Th1) cytokines (e.g., IL-2, IL-12, and IL-15), genetic engineering of DCs to overexpress T helper 2 (Th2) cytokines such as IL-4 and IL-10 has also been explored75,76,77. For example, transducing DCs with IL-4 could lead to augmented antibody responses by orchestrating the differentiation of CD4+ Th2 cells and B cells78. These approaches to utilizing DCs to produce and release cytokines locally could lead to enhanced CTL and humoral responses and improved therapeutic efficacy while reducing the off-target side effects of conventional cytokine therapies.

Fig. 5: Overexpression of cytokines in and on DCs.
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a Cytokines can be overexpressed through the genetic engineering of DCs and subsequently released. (b) Cytokines overexpressed in DCs are released and affect neighboring T and B cells. c Overexpressed cytokines can be displayed on DC membranes to directly orchestrate the priming processes of T and B cells while avoiding the systemic release of cytokines.

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Overexpression of cytokines on the DC membrane

While overexpressing cytokines inside DCs and utilizing engineered DCs to release produced cytokines have shown great promise for improving the overall CTL response with reduced side effects, issues regarding the systemic release of cytokines from engineered DCs remain79. Additionally, compared with the paracrine release of intracellular cytokines, the surface display of T/B-cell-effector cytokines could provide a unique approach to regulate the intercellular interactions between DCs and T/B cells (Fig. 5c)80. In view of these findings, efforts have been made to overexpress cytokines on the membrane of DCs. The substantial progress in the field of genetic engineering over the past few decades has provided powerful tools to overexpress different types and amounts of cytokines on DCs. The surface expression of cytokines (e.g., IL-2, IL-12, and IL-15) can be achieved by transducing DCs with a plasmid that encodes a fusion protein of the cytokine and a transmembrane domain80. The membrane-bound cytokines on DCs can directly modulate interacting T and B cells in a juxtacrine manner81. In this approach, DCs can simultaneously present MHC antigens, costimulatory signals, and cytokines to interacting immune cells, such as T and B cells, to drive improved priming of antigen-specific T and B cells. Compared with soluble cytokines in the surrounding milieu, membrane-displayed cytokines can stimulate interacting T and B cells in a timely manner and likely require a much lower concentration to achieve a comparable or better T/B-cell priming effect. For example, by transducing DCs with membrane-bound IL-12, engineered DCs significantly improved the stimulation of CD8+ T cells and the polarization of Th1 cells in the tumor microenvironment, resulting in a minimal concentration of IL-12 in the bloodstream82. Compared with soluble cytokines, membrane-bound IL-4 was also shown to stimulate IL-12 production in adjacent antigen-presenting cells and lead to enhanced antitumor efficacy83. These findings suggest that the overexpression of cytokines in membrane-bound forms represents a viable strategy to improve therapeutic efficacy while reducing off-target side effects.

Surface conjugation of cytokines to DCs

In addition to genetic engineering methods to overexpress cytokines on DC membranes, methods that involve the direct conjugation of cytokines onto DC membranes have also been explored (Fig. 6a). Compared with genetic engineering methods, these chemical approaches are simpler and avoid the safety concerns associated with viral transduction84,85. Conventional strategies to chemically attach cargos to the cell membrane either utilize hydrophobic or electrostatic interactions between cargos and the DC membrane or leverage amine‒carboxyl chemistry86,87. For example, lipid molecules with hydrophobic tails (e.g., dioleoyl, dipalmitoyl, or dimiristoyl lipids) can insert into the lipid bilayer structure of cell membranes. Cargos, via simple modification with N-hydroxysuccinimide (NHS) ester functional groups, can be directly conjugated to amine-bearing glycoproteins and glycolipids on the cell membrane88,89,90.

Fig. 6: Cell surface modification methods for engineering DCs.
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a Schematic illustration of the conjugation of cytokines to surface-modified antigen-presenting DCs and the subsequent priming of T cells. b Metabolic labeling of DCs with azido groups via the metabolic glycoengineering process of unnatural sugars for the subsequent conjugation of cytokines via efficient click chemistry. Adapted from Han et al.94.

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DCs can also be metabolically labeled with clickable chemical tags (e.g., azido groups) via the metabolic glycoengineering process of unnatural sugars for the subsequent conjugation of cytokines via efficient and bioorthogonal click chemistry91,92. Upon endocytosis by DCs, unnatural sugars bearing unique functional groups can undergo metabolic glycoengineering, conjugate to proteins and lipids, and become expressed on the cell membrane in the form of glycoproteins and glycolipids93. For example, DCs can be metabolically labeled with azido groups via treatment with tetraacetyl-N-azidoacetylmannosamine (Ac4ManAz) or poly(azido-sugar). The cell-surface azido groups can then capture dibenzocyclooctyne (DBCO)-modified cytokines (e.g., IL-2 and IL-15) via efficient click chemistry (Fig. 6b)31,94. This approach enables the targeted conjugation of cytokines to DCs in vitro and in vivo. The cytokines displayed on the surface of DCs can provide a continuous activation signal to interacting T cells for improved T-cell priming. Compared with nonconjugated DCs, IL-2- or IL-15-conjugated DCs resulted in an enhanced CTL response and antitumor efficacy in mouse models of lymphoma and melanoma31,94.

Conclusion and Future Perspectives

Cytokines are crucial for the survival, proliferation, and differentiation of immune cells, as well as for regulating interactions among diverse immune cell types. However, despite the FDA approval of IFN-α and IL-2 for cancer treatment, conventional cytokine therapy is associated with low response rates and high toxicity. The use of DCs as the cytokine carrier via the forced overexpression of cytokines in DCs has emerged as a promising strategy to concentrate cytokines at the interface of DCs and T/B cells and thus amplify the generation and expansion of antigen-specific T and B cells. This approach can potentially reduce the doses of cytokines and associated side effects to achieve an enhanced CTL response and antitumor efficacy. Depending on the plasmid design, the overexpressed cytokines can either be released from DCs to exert a paracrine effect on interacting T and B cells or be displayed on DC membranes to modulate DC–T/B-cell interactions in a juxtacrine manner. At present, IL-2, IL-15, IL-12, IFN-α, and IL-4 are the most commonly studied cytokines, and the overexpression of various other types of cytokines in DCs could provide new opportunities for the modulation of T- and B-cell priming processes and the development of improved immunotherapies. Viral transduction is the most commonly used method for the forced expression of proteins in cells such as DCs because of the high transfection efficiency and availability of standard protocols. However, safety concerns related to viral transduction methods remain for potential clinical translation. The delivery of mRNAs could provide a safer and viable approach for the overexpression of cytokines in DCs in future efforts. Additionally, the substantial progress in mRNA chemistry over the past decades has enabled the design of mRNAs that encode cell-secreted proteins or surface-displayed proteins95.

In addition to the overexpression of cytokines in DCs via genetic engineering methods, recent advances in the chemical modification of cell membranes have opened new opportunities for the facile display of cytokines on DCs. The attachment of a hydrophobic lipid moiety to cytokines can improve their insertion into cell membranes via hydrophobic interactions, although the membrane retention time varies with the type of molecule. Endogenous functional groups (e.g., amino groups) from cell-surface proteins, lipids, or saccharides also enable the covalent conjugation of cytokines, but the conjugation efficiency is often limited by the low density of cell-surface reactive functional groups. Metabolic glycan labeling technology has provided a facile yet powerful approach for introducing clickable chemical tags (e.g., azido groups) onto the membrane of DCs for the subsequent conjugation of cytokines via efficient click chemistry. This method enables the display of tunable amounts of cytokines on the surface of DCs for the direct modulation of interacting T and B cells and has shown promise for improving the overall CTL response and antitumor efficacy against various types of cancer. Further endeavors will seek to further understand and optimize the stability, conformation, and membrane retention time of cytokines introduced onto DC membranes to more precisely orchestrate the interactions between DCs and T/B cells.

The choice of the type of cytokine for overexpression in DCs is inevitably critical and requires scrutiny for different scenarios of DC–T/B-cell interactions in the context of different cancers. The specific subtypes of T cells, such as CD8+ T cells, CD4+ effector T cells, and regulatory T cells, targeted by engineered DCs are key considerations. Equally important is the choice of releasing the overexpressed cytokines in a paracrine manner or displaying the cytokines on DC membranes, depending on the specific need of each scenario. At present, one cannot predict the ideal dose of cytokines that DCs should display to the interacting T and B cells for the optimal CTL response and antitumor efficacy. More efforts are needed to decipher the immune synapse between DCs and T/B cells and the mechanism underlying the cytokine-mediated modulation of those interactions. Nevertheless, the use of DCs as carriers of cytokines holds great promise for maximizing the impact of T/B-cell-effector cytokines while reducing the needed dose and associated toxicity compared with conventional cytokine therapies. A comprehensive investigation of how cytokines released or displayed by DCs dictate the phenotypes, activation status, and functions of T and B cells will also provide an improved understanding of the T- and B-cell priming processes and guide the design of new immunotherapies.

The DC vaccine, which involves ex vivo engineering of DCs with tumor antigens and cytokines, was among the first FDA-approved cancer immunotherapy ies (i.e., Sipuleucel-T). However, the modest therapeutic benefit (4.1-month improvement in the median survival of patients with prostate cancer) has hindered its wide use96. Over the past two decades, various other types of cancer vaccines, including tumor lysate vaccines, tumor exosome vaccines, nanovaccines, biomaterial scaffold vaccines, mRNA vaccines, and DNA vaccines, have been developed, but their antitumor efficacy is still far from satisfactory, and their clinical translation has been slow97,98. DC vaccines are still among the most promising cancer vaccine platforms for clinical translation, with one product already receiving FDA approval99. Indeed, extensive efforts have been made to improve the manufacturing and culture of DCs, optimize the subtypes of DCs, and enhance the in vivo persistence of DCs after adoptive transfer100. The overexpression of cytokines in DCs, as described in this review, represents a promising approach to increase the therapeutic benefits of DC vaccines and other DC-based immunotherapies.