The role of platelets in tumor immune evasion and metastasis: mechanisms and therapeutic implications

Abstract

Only circulating tumor cells (CTCs) that successfully evade immune surveillance upon entering the bloodstream can lead to clonal expansion and metastasis. Cancer progression is accompanied by pathophysiological processes such as platelet activation and thrombosis. Platelets secrete a variety of growth factors to stimulate cancer cell proliferation, regulate tumor angiogenesis, and subsequently mediate surface changes in cancer cells to promote invasion and progression. As part of a dangerous alliance, CTCs and platelets induce mutual activation. Activated platelets aggregate and encapsulate tumor cells, forming microtumor thrombi containing fibrin clots that act as protective barriers. These platelets interact with immune cells, including NK cells, macrophages, neutrophils, and T cells, to facilitate cancer metastasis and progression through various mechanisms. The formation of a favorable tumor microenvironment (TME) and pre-metastatic niche aids cancer cells in evading immune surveillance. Multiple signaling pathways and immune checkpoints are also involved in this process. Given the significant role of platelets in tumor immune evasion, anti-cancer strategies targeting platelets and their potential use as "bionic drug delivery systems" for anti-tumor drugs hold broad prospects in emerging tumor therapies.

Keywords: CTC; Immune cell; Immune escape; Platelet; Signaling pathway; Therapy.

Fig. 1

Interactions between platelets and tumor cells can lead to platelet activation and aggregation, thereby promoting the formation of TEPs (right panel). Concurrently, these interactions facilitate tumor progression through the release of multiple platelet-derived microparticles and their associated contents (left panel). The cross-talk between platelets and circulating tumor cells (CTCs) is primarily mediated by several receptor-ligand pairs, including GPIIb/IIIa (integrin αIIbβ3) - αVβ3, P-selectin - PCLP1 (podoplanin-like protein 1)/PSGL-1 (p-selectin glycoprotein ligand 1)/mucin/CD44, glycoprotein VI (GPVI) - galectin-3, C-type lectin-like receptor 2 (CLEC-2) - podoplanin (PDPN), GPIbα - vWF, and ADAM9 - integrin α6β1. Reprinted from [17]

Fig. 2

Mechanisms of platelet education within the tumor microenvironment

Fig. 3

A. Tumor cells facilitate immune evasion through interactions with CD94-NKG2A on NK cells. Upon upregulation of RGS18, AKT phosphorylation is attenuated, leading to the stabilization of GSK3β by inhibiting serine residue 9 phosphorylation. Subsequently, GSK3β enhances CREB1 activity via phosphorylation at serine residue 133. Activated CREB1 exhibits predominantly nuclear subcellular localization and forms a transcriptional positive regulatory complex with RFX and NFY within the nucleus. This complex binds to the HLA-E promoter, which contains intact SXY modules and partial enhancer A and ISRE sites. Consequently, overexpression of RGS18 results in increased HLA-E levels in three PDAC cell lines. B. Platelets mediate tumor cell resistance to apoptosis through various mechanisms