Eliciting antitumor immunity via therapeutic cancer vaccines

Abstract

Therapeutic cancer vaccines aim to expand and activate antigen-specific T cells for the targeted elimination of cancer cells. While early clinical trials faced challenges due to suboptimal antigen-specific T-cell activation, recent advancements in antigen discovery and vaccine platform engineering have revitalized the field. This review provides a comprehensive overview of key tumor antigens, including tumor-associated antigens, viral oncoprotein antigens, neoantigens, and cryptic antigens, with a focus on their immunogenicity and therapeutic potential. Advances in our understanding of traditional cancer vaccination targets, in conjunction with the timely identification of novel antigen epitopes, have facilitated the strategic selection of vaccination targets. We also discuss the evolution of cancer vaccine platforms-spanning peptide-based formulations to advanced mRNA vectors-emphasizing innovative strategies to optimize antigen delivery efficiency and adjuvant effects. Efficient antigen delivery and adjuvant selection overcome immune tolerance and tumor-induced immunosuppression. Furthermore, we examine recent clinical trial data and emerging combination approaches that integrate cancer vaccines with other immunotherapies to increase efficacy. While significant progress has been made, challenges remain in improving vaccine-induced T-cell responses, overcoming immune suppression, and translating these advances into effective clinical interventions. Addressing these hurdles will be critical for realizing the full potential of cancer vaccines in immunotherapy.

Keywords: Cancer immunotherapy; Neoantigen; Tumor-associated antigen; Vaccine.

Fig. 1

Cancer Antigen Categories and Personalized Neoantigen Vaccine Design. A Tumor antigens can be roughly classified into five categories: tumor-associated antigens (TAAs), cancer/testis antigens, oncoviral antigens, neoantigens, and cryptic antigens. The table summarizes the key properties of each category, including tumor specificity, central tolerance, patient prevalence, clonality among cancer cells, and clinical exploration. Notable examples are also provided. B Clinical procedure for designing personalized neoantigen vaccines. Tumor and normal tissue (e.g., PBMC) biopsies are obtained from patients and sent for next-generation sequencing (NGS) and mutation calling. The identified nonsynonymous mutations are evaluated for MHC binding, antigen presentation, transcript levels, self-dissimilarity, and clonality. Selected neoantigen epitopes are synthesized into peptide or mRNA vaccines for patient treatment

Fig. 2

Antigen presentation of cancer vaccines. Peptide vaccines: Synthetic long peptides (SLPs) and adjuvants, such as Toll-like receptor (TLR) agonists, are injected to stimulate an immune response. Antigen-presenting cells (APCs) take up SLPs, process them via cross-presentation pathways, and present peptide‒MHC complexes to T cells. Adjuvants activate APCs, increasing the expression of costimulatory markers such as CD80/86 and promoting their migration to lymph nodes, where they prime and activate T cells. mRNA vaccines: mRNA vaccines encoding tumor antigens are internalized by dendritic cells (DCs) via endocytosis or macropinocytosis, followed by endosomal escape and cytosolic release of mRNA facilitated by ionizable lipids. Within the cytoplasm, mRNAs are translated into antigens, which are subsequently processed into epitopes and presented on the cell surface through interactions with MHC molecules. During this process, the mRNA vaccine might activate innate immune pathways, including TLR7, MDA5, or RIG-1, thereby stimulating innate immune responses. These antigen-presenting DCs then prime antigen-specific T cells, which differentiate into either memory T cells or effector T cells, thereby inducing tumor cell death

Fig. 3

Developmental trajectory of peptide vaccines. Upper panel: Early clinical peptide vaccine formulations combining minimal CD8 ⁺ T-cell epitopes with adjuvants such as incomplete Freund’s adjuvant (IFA), creating an antigen “depot” at the injection site. However, this leads to antigen presentation by nonprofessional APCs, causing sustained chronic inflammation at the injection site. Antigen-specific T cells accumulate at the injection site and undergo tolerance and dysfunction. Middle panel: Many current clinical trials use synthetic long peptides (SLPs) mixed with Toll-like receptor (TLR) agonists, such as polyICLC. SLPs promote antigen presentation by professional APCs and may contain CD4 ⁺ T-cell epitopes, which help recruit CD4⁺ T cells to assist in CD8 ⁺ T-cell priming. This improves T-cell priming and effector T-cell generation. However, owing to the small size of TLR agonists and SLPs, most of the injected reagents leak into the circulation, with limited antigen and adjuvant uptake by APCs. Additionally, some TLR agonists can induce systemic proinflammatory responses, resulting in toxicity. Lower panel: New-generation peptide vaccines use particulate delivery systems for antigens and adjuvants, which improve lymphoid tissue targeting. Antigens and adjuvants can be designed to self-assemble into nanometer-scale complexes or be incorporated into lipid-based nanoparticles, which are preferentially taken up by APCs. This design allows for the efficient codelivery of antigens and adjuvants, reducing systemic inflammatory responses and inducing robust T-cell responses. However, large-scale production and quality control of lipid nanoparticle-based vaccines remain significant challenges. Another strategy involves conjugating peptides or adjuvants to moieties that bind albumin, which increases APC uptake and enhances T-cell responses

Fig. 4

Developmental trajectory of cancer mRNA vaccines. Early clinical trials of mRNA vaccines focused on the direct injection of unmodified, naked mRNA via intranodal administration. However, this approach faces many challenges, including the instability and high immunogenicity of mRNAs, low transfection efficiency into antigen-presenting cells (APCs), and low protein production. Therefore, some formulated vectors, such as cationic protamine and liposomes, have been developed to encapsulate unmodified mRNAs. While these formulations improve mRNA stability and transfection efficiency in vitro, their in vivo efficacy remains constrained by low transfection efficiency and protein production and the toxicity associated with cationic components. More recently, LNP- or LPX-encapsulated mRNA vaccines have been frequently utilized, along with modified (m1ψ) mRNAs, which exhibit reduced immunogenicity. Thus, the transfection efficiency and protein production are enhanced in vivo. These mRNA vaccines are generally well tolerated and possess inherent adjuvant effects that stimulate innate immune responses, triggering antigen-specific T-cell activation. Moreover, certain delivery systems, such as spleen-targeting mRNA-LPX, can deliver mRNAs more specifically to the spleen