Anti-tumor Vaccine Efficacy Related to Glycan Profile
On October 6, 2025, Marc Ehlers et al. from the University of Lübeck in Germany published an article titled "Anti-tumor vaccine efficacy depends on adjuvant type and associates with induced IgG subclass and glycosylation profiles" in Experimental Hematology & Oncology. This study systematically compared the protective effects of various Vaccine Adjuvants in tumor models and found that antibody glycoform composition was a stronger predictor of vaccine efficacy than antibody titer. The proportion of IgG subclasses and glycosylation patterns induced by different adjuvants determine whether the anti-tumor effect is primarily dependent on NK cells or neutrophils, suggesting that future tumor vaccine design should focus on inducing the right antibody type, rather than simply boosting antibody levels.
The core goal of tumor vaccines is to precisely eliminate tumor cells by activating T and B cells in the body through the injection of tumor antigens combined with immune adjuvants. However, traditional research often focuses on the amount of antibodies induced or the number of T cells activated, overlooking a crucial aspect: Antibodies are not simply about quantity; their quality, particularly the IgG subclass and its Fc region glycosylation pattern, significantly determines the strength and pathway of their anti-tumor effects.
This study, based on a mouse model, systematically evaluated the effects of several commonly used vaccine adjuvants (including Alum, Poly(I:C), MPLA, IFA, CFA, and eCFA) on antibody responses and explored their correlation with anti-tumor protection. The study revealed that different adjuvants not only induce different IgG subclasses but, more importantly, differentially regulate the N-Glycosylation patterns of the Fc region, particularly the ability to induce fucose-deficient (F0) IgG1. F0 IgG1 has stronger Fcγ receptor binding and is considered a key driver of effector functions such as ADCC.
More importantly, while various adjuvants can induce anti-tumor protection, their mechanisms of action vary. Taking Poly(I:C) as an example, its protective effect relies primarily on a high IgG2/IgG1 ratio and high galactosylation/sialylation, exerting its effects through the NK cell pathway. In contrast, antibodies induced by eCFA exhibit low galactosylation/sialylation, favoring neutrophil activation, thereby achieving tumor clearance.
Thus, this study not only reveals the critical linkage between adjuvant, antibody glycoforms, and effector cells, but also provides a clear direction for future tumor vaccine design: truly effective vaccines should focus on inducing specific antibody glycoforms rather than simply boosting antibody titers.
Vaccine adjuvants are crucial ingredients for enhancing immune responses, determining not only the intensity but also the type of immune response. Previous research on tumor vaccines has primarily focused on Th1 and CD8⁺ T cell responses, which are considered the primary drivers of cytotoxic immunity. However, growing evidence indicates that antibody-mediated humoral immunity also plays a key role in anti-tumor responses. Furthermore, the effector function of an antibody depends not only on its Fab region, which recognizes tumors, but also on how its Fc structure binds to effector cells. This binding ability is determined by IgG subclass and Fc glycosylation.
The N297 glycan in the IgG Fc region can undergo four primary modifications: Fucose, galactose, bisecting GlcNAc, and sialic acid. Studies have demonstrated that defucosylation (F0) significantly enhances the ADCC activity of IgG1/IgG3 in humans, with similar effects observed in mouse IgG2a/c and IgG2b. Therefore, antibodies with a high F0 ratio are considered more potent and effective in anti-tumor responses.
However, it remains unclear whether vaccine adjuvants can systemically induce F0 antibodies and whether this induction is memory-dependent. Furthermore, the role of other glycoform modifications, such as galactosylation and Sialylation, in anti-tumor immunity is more complex. Studies have shown that they may enhance NK cell activation or inhibit inflammatory responses, so their specific roles require further exploration. This study addresses this scientific question: Do different adjuvants exhibit unique antibody glycoform regulation? Does this regulation determine whether the ultimate anti-tumor mechanism is mediated by NK cells, macrophages, or neutrophils?
Fig. 1 Anti-tumor vaccine efficacy depends on adjuvant type and associates with induced IgG subclass and glycosylation profiles. (Lehrian, et al. 2025)
Whether it is the Th2 adjuvant Alum, the Th1 adjuvant Poly(I:C), or even the Th17 adjuvant eCFA, a transient increase in antigen-specific IgG1 F0 (up to 5%) was detected after the initial immunization of mice. This suggests that defucosylation is not an effect unique to any single adjuvant but rather a common phenomenon in the early stages of immune activation.
After a single immunization, the F0 peak induced by most adjuvants rapidly disappears. However, when mice are re-exposed to the antigen without adjuvant, only the Poly(I:C) and eCFA groups are able to re-elicit a F0 IgG1 increase. This suggests that these two adjuvants not only induce an initial F0 response but also establish a memory glycoform response, which may persist during long-term tumor antigen exposure.
When researchers further elucidated the mechanism through passive serum transfer experiments, they found that the anti-tumor effects of serum from the Poly(I:C) group were highly dependent on NK cells, while serum from the eCFA group retained some effect even after NK cell depletion, with a preference for neutrophil-mediated killing.
This was highly correlated with their Glycosylation Profiles. This suggests that different adjuvants do not simply differ in immune potency but rather direct antibodies to different immune pathways.
The researchers further validated the results using an engineered anti-TRP1 IgG2a antibody, prepared in two forms: a "galactosylated" and a "galactosylated and sialylated" form. The results showed that both exhibited significant anti-tumor effects, but speculated that they may function through different cell types, consistent with the patterns observed in the adjuvant experiments.
This study systematically reveals for the first time the key linkages between vaccine adjuvant type, IgG subclass, glycosylation pattern, and effector cell type, proposing the following key insights:
Antibody titer is not the key metric for evaluating cancer vaccine efficacy; the antibody glycoform truly determines the quality of the immune response. Defucosylated IgG1 (F0) is universally inducible, but only certain adjuvants can establish a glycoform memory response. Different glycosylation profiles determine whether antibodies recruit NK cells or neutrophils.
This discovery not only provides a scientific basis for the design of various current Cancer Vaccines (including mRNA vaccines, peptide vaccines, and vector vaccines), but also suggests new optimization directions for antibody drug engineering. If Fc glycoform monitoring can be incorporated as an immunological assessment metric in future clinical studies, we may be able to truly understand which vaccines merely stimulate immunity and which vaccines can achieve sustained tumor clearance.
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