Tissue-resident immune cells in cervical cancer: emerging roles and therapeutic implications

Abstract

The favorable prognosis of "hot" tumors is widely acknowledged in oncology. Recently, the concept of tertiary lymphoid structures (TLS) has renewed appreciation for local immune cells within tumor tissues. Tissue-resident immune cells, a newly identified subset of tumor-infiltrating lymphocytes, are emerging as potential key players in tumor infiltration and TLS formation, due to their ability to reside indefinitely within tissues and mount effective responses to local antigens. Cervical cancer (CC), the fourth most common cause of cancer-related mortality among women globally, has experienced comparatively limited progress in delineating its tumor immune microenvironment compared to other malignancies. Notably, the role of tissue-resident immune cells within the CC milieu remains inadequately characterized. This comprehensive review aims to synthesize current knowledge and critically evaluate the putative roles of these cells in CC pathogenesis, providing new insights on the intricate dynamics of the local tumor microenvironment.

Keywords: Trm cell differentiation; cervical cancer; local tumor microenvironment; tissue-resident immune cells; tissue-resident memory T cells.

Figure 1

The development of Trm cells in CC. Migratory dendritic cells (DCs) capture tumor antigens within the tumor microenvironment (TME) and migrate to draining lymph nodes. There, they present these antigens to naïve T cells via MHC class molecules, initiating T cell activation and differentiation. Concurrently, DCs secrete cytokines, notably TGF-β, and metabolites like vitamins A and D, which influence T cell fate during the priming phase. Following activation, Trm precursors enter the arterial circulation, guided by chemokines (e.g., CCL5, CXCL9, CXCL10) that direct them toward tumor tissues. The upregulation of CD69 on Trm precursors inhibits S1PR1 signaling, preventing their return to circulation and anchoring them within the TME. Within this environment, Trm precursors undergo final differentiation, driven by a network of inflammatory cytokines and tumor antigen re-stimulation. Created in BioRender. Li, Q. (2025) https://BioRender.com/kfcf5cr.

Figure 2

The potential role of tissue-resident immune cells in CC. CD8⁺Trm cells are characterized by high expression of inhibitory receptors and activation markers, including CD39, LAG3, PD-1 (PDCD1), TIM-3, and TIGIT, indicating their tumor antigen specificity and activation status. They demonstrate significant local expansion within tumor tissues, contributing directly to anti-tumor immunity through cytotoxic activity against tumor cells. CD4⁺Trm cells play a pivotal role in supporting CD8⁺Trm cells by the release of cytokines such as IFN-γ, TNF-α and chemokine CXCL13, which facilitate the recruitment and activation of other immune cells. Tissue-resident NK Cells exhibit robust cytokine production capabilities, participating in tumor immune regulation. The significant upregulation of GZMK distinguishes them from conventional NK cells, underscoring a unique functional profile that may contribute to enhanced anti-tumor responses. Tissue-resident B Cells are categorized into CD69⁺B cells and CD103⁺B cells. The presence of the CD69⁺B cell subset indicates the acquisition of local residency and memory capabilities within tumor tissues. The differentiation tendency of CD69⁺B cells toward CD103⁺B cells suggests heightened specificity for tumor antigens and a substantial role in TLS formation, thereby amplifying the humoral immune response against the tumor.