Platelets in cancer and immunotherapy: functional dynamics and therapeutic opportunities

Abstract

Platelets play a critical role in tumor immunity, particularly in promoting cancer progression. Numerous studies suggest that platelets could serve as a novel target for cancer immunotherapy, however, no comprehensive reviews have yet summarized and discussed this potential. Our review provides an in-depth discussion of the roles and mechanisms of platelets within both the immunosuppressive tumor microenvironment and the anti-tumor immune microenvironment. Additionally, we summarize the key therapeutic targets and approaches for clinical translation. This work offers essential insights for reprogramming platelets to shift their function from tumor promotion to tumor suppression, providing a foundation for the development of novel immunotherapeutic strategies and related research.

Keywords: Cancer; Immunotherapy; Platelet; Tumor microenvironment.

Fig. 1

Platelets protect CTCs from NK cell elimination. Once tumor cells enter the bloodstream, platelets rapidly aggregate around them, forming a protective barrier that shields CTCs from NK recognition. This platelet encapsulation leads to upregulation of inhibitory receptor ligands, such as HLA-E on CTC, while simultaneously downregulating ligands for activating receptor like NKG2D. This dual modulation effectively inhibits NK cell-mediated tumor cells killing. Moreover, platelets exhibit increased expression of RANKL, which binds to the inhibitory RANK on NK cells, further suppressing their cytotoxic activity. Additionally, GITRL has been observed to transfer from tumor cells to the surface of platelets, further contributing to the immune evasion. CD, cluster of differentiation; CTC, circulating tumor cell; HLA, human leukocyte antigen; GITRL. glucocorticoid-induced TNFR-related protein ligand; NK, natural killer; NKG2, natural killer group 2; RANK, receptor activator of nuclear factor-kappa B; TIGIT, T cell immunoreceptor with Ig and ITIM domain

Fig. 2

Platelets and TGF-β in shaping immunosuppressive TME. Tumor cells are found to transfer PD-L1 to the surface of platelets, thereby inhibiting T cell-mediated immune response. The level of PD-L1 is elevated by platelet releases, including PGE2 and TPH1. Additionally, TLT1, PF4, and Erbin have been demonstrated to impair the functions of T cells and B cells, respectively. Platelets also positively influence CAFs, causing increased interstitial pressure in tumor stroma. In addition, the release of active TGF-β from the GARP-LTGF-β complex on platelets is elevated, promoting pro-tumor cells such as M2 macrophages, MDSCs and TANs, while simultaneously inhibiting cytotoxic T cell, thus enabling immune exclusion. All these effects collectively contribute to an immunosuppressive TME. CAF, cancer associated fibroblasts; DC, dendritic cell; GARP, glycoprotein-A repetitions predominant; LTGF-β, latent transforming growth factor beta; GP, glycoprotein; MDSC, myeloid-derived suppressor cell; PD-L1, programmed cell death ligand 1; PF4, platelet factor 4; PGE2, prostaglandin E2; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil; TLT-1, TREM-like transcript 1; TME, tumor microenvironment; TPH1, tryptophan hydroxylase 1

Fig. 3

The role of platelets in anti-cancer immunity. Platelets act as a be a bridge between innate and adaptive immunity. They promote the differentiation of monocytes into anti-cancer M1 macrophages. Platelet-derived PDGF-DD supports the survival and function of NK cells. Interestingly, megakaryocytes and pro-platelets, the precursors of platelets, express MHC hI molecules, allowing them to recognize both exogenous and endogenous antigens. Platelets can shuttle antigens within the circulation and deliver them to DCs, facilitating DC maturation and subsequent cell activation, thereby eliciting an adaptive immune response. The expression of CD154 on platelets interacts with CD 40 on multiple immune cells, such as T cells, to enhance their anti-cancer effects. Additionally, platelets have been shown to induce the isotype switching of B cells, bolstering their ability to combat infections and malignancies. CD, cluster of differentiation; DC, dendritic cell; MHC, major histocompatibility complex; NK, natural killer; PDGF, platelet-derived growth