Overcoming the novel glycan-lectin checkpoints in tumor microenvironments for the success of the cross-presentation-based immunotherapy.

In pursuit of meeting the ever-rising demand for cancer therapies, cross-presentation-based glyconanovaccines (GNVs) targeting C-type lectin receptors (CLRs) on DCs have shown significant potential as cutting-edge cancer immunotherapy. GNVs are an attractive approach to induce anti-cancer cytotoxic T lymphocyte responses. Despite immune checkpoints (ICs) being well established and an obstacle to the success of GNVs, glycan-lectin circuits are emerging as unique checkpoints due to their immunomodulatory functions. Given the role of aberrant tumor glycosylation in promoting immune evasion, mitigating these effects is crucial for the efficacy of GNVs. Lectins, such as siglecs and galectins, are detrimental to the tumor immune landscape as they promote an immunosuppressive TME. From this perspective, this review aims to explore glycan-lectin ICs and their influence on the efficacy of GNVs. We aim to discuss various ICs in the TME followed by drawbacks of immune checkpoint inhibitors (ICIs). We will also emphasize the altered glycosylation profile of tumors, addressing their immunosuppressive nature along with ways in which CLRs, siglecs, and galectins contribute to immune evasion and cancer progression. Considering the resistance towards ICIs, current and prospective approaches for targeting glycan-lectin circuits and future prospects of these endeavors in harnessing the full potential of GNVs will also be highlighted.