Cancer immunotherapies based on T cells through the restoration of host anti-tumor immune responses have witnessed unprecedented advances in the last decade, which has transformed the treatment paradigm for multiple tumor types (1). Despite impressive therapeutic efficacy in subsets of patients, most patients exhibit innate or acquired resistance to these therapies (1). Mounting clinical evidence has indicated that abundant infiltration of malignant lesions by immune effector cells is a prerequisite for recognizing and killing tumor cells (2). However, these immune effector cells are largely excluded from the tumor microenvironment (TME), partly caused by abnormal alterations of the angiogenic vasculature, which highlights the essential role of tumor vasculature in anti-tumor immunity and immunotherapies (3).

A particular form of vasculature is high endothelial venules (HEVs) which are specialized and organ-specific postcapillary venules (4). HEVs express high levels of peripheral node addressing (PNAd) that are identified by the HEV-specific antibody MECA-79, which is uniquely poised to mediate the capture and rolling of lymphocytes towards secondary lymphoid organs like lymph nodes (LNs) (4). The HEV network expands during inflammation in immune-stimulated LNs and is profoundly remodeled in metastatic and tumor-draining LNs, facilitating the amplification and maintenance of chronic inflammation (5). HEVs can also form ectopically in a wide variety of cancers, usually surrounded by dense infiltration of lymphocytes organized into lymph-node-like, T- and B-cell-rich areas referred to as tertiary lymphoid structures (TLSs) (6). Multiple studies have demonstrated a close correlation between HEV density and the density of TLSs (7, 8). As a special component of TLSs, tumor-associated HEVs (TA-HEVs) serve as gateways for the recruitment of lymphocytes to TLSs, and once recruited, naive lymphocytes are activated locally by tumor antigens (7). The formation of TA-HEVs may overcome the major barrier of immune effector cell exclusion from the TME, providing attractive avenues to induce and sustain the efficacy of immunotherapy (9). Many studies have found positive correlations between TA-HEVs and favorable prognosis in various types of cancer, such as non-small cell lung cancer, melanoma, breast cancer, and colorectal carcinoma (10). However, the opposite effect has been reported for TA-HEVs in many tumors like colorectal cancer (11) and gastric cancer (12). Thus, the clinical significance of TA-HEVs across various solid tumors remains controversial, which poses a major obstacle to their clinical application as biomarkers to accurately predict prognosis and immunotherapy response.

However, no meta-analysis has thus far been conducted to assess the role of TA-HEVs in solid tumors. To address this gap, we performed this pooled analysis for the first time to comprehensively explore the prognostic value of TA-HEVs and determine their relationships with clinicopathological features in solid tumors.

We performed this study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (13). Additionally, this study has been registered in PROSPERO (registration number: CRD42023394998).

The lack of sufficient pre-existing intratumoral lymphocyte infiltration poses a major obstacle to effective immunotherapies, with tumor-infiltrating lymphocytes being strongly associated with improved clinical outcomes in various cancers (3). TA-HEVs may offer attractive avenues to initiate and sustain effective immunotherapies by overcoming immunocyte exclusion from the TME (8).TA-HEVs are considered to be of great importance in recruiting naive T cells and B cells into the tumors, and locally enhancing anti-tumor immunity by fostering the formation of TLSs (7). However, the prognostic significance of HEVs among various studies is still controversial. This study, for the first time, systematically investigated the prognostic values of TA-HEVs and determined their relationships with clinicopathological features in solid tumors.

To systematically elucidate the prognosis role of TA-HEVs in solid tumors, data were pooled from 13 studies involving 1,933 patients in the present study. The pooled analysis demonstrated TA-HEVs might be favorable prognostic biomarkers in solid tumors, with positive TA-HEVs being significantly correlated to better survival outcomes regarding OS and DFS. Moreover, sensitivity analysis and publication bias tests indicated that these results were stable and credible. Correspondingly, a positive correlation has been observed between TA-HEV density and tumor remission in patients with cutaneous melanoma (27). The presence of TLSs comprising TA-HEVs was reported to be an independent prognostic biomarker for pancreatic ductal adenocarcinoma patients treated with neoadjuvant chemotherapy (NAC), possibly resulting in a better prognosis (28). Song IH et al. (17) proposed that the high density of TA-HEVs not only predicted the pathologic complete response but was also a predictor of improved DFS in TNBC patients receiving NAC. A recent study conducted by Asrir A et al. (23) revealed that high numbers of TA-HEVs in pre-treatment metastatic lesions were associated with better clinical response and survival of melanoma patients undergoing combined immune checkpoint inhibitors (ICI) therapy. These findings are in line with the crucial role of HEVs as major portals for lymphocyte infiltration into tumors. Studies of multiple human malignancies have confirmed that lymphocyte infiltration specifically at HEV-rich areas of the tumors, and a strong correlation between HEV density and densities of tumor-infiltrating CD3⁺ T cells, CD8⁺ T cells, and CD20⁺ B cells (4, 10). TA-HEVs have been confirmed to be the main sites of lymphocyte tethering, rolling, and sticking in the tumor microcirculation both at baseline and during combined ICI therapy (23). Analysis of tumor biopsies from 93 metastatic melanoma patients revealed that high numbers of TA-HEVs were related to better survival and clinical response of patients treated with combined immunotherapy (23). A real-world retrospective study in advanced non-small cell lung cancer indicated that PNAd⁺ TA-HEVs were predictive of better response and survival upon PD-1 blockade combined with anti-angiogenesis therapy (29).

In the vast majority of our results, heterogeneity was not significant among the different studies, indicating that TA-HEVs have broad applicability across different populations and tumor types. Nonetheless, we still explored the potential source of heterogeneity based on PRISMA Guidelines. Subgroup analysis identified that ethnicity and source of HR might be potential sources of heterogeneity, with P-values of subgroup difference test less than 0.05. It was also found that the critical value of sample size (≥200), tumor type (others), and cut-off criteria with non-median values had no significant relationship with OS. This might be why the small sample size, limited studies, and non-uniform cut-off criteria could not reveal the real results. Notably, Recent studies suggested varying degrees and stages of TA-HEV maturation might imply functional differences among intertumoral MECA-79⁺ vessels. And, plump TA-HEVs surrounded by massive lymphocyte aggregates assumed to be more mature in comparison to some flat and isolated TA-HEVs located at the periphery (8). Moreover, it was worth noting that TA-HEV-related TLSs predominantly aroused at the tumor periphery or the tumor interphase, while HEVs in the tumor center were very rare and not correlated with well-organized immune cell aggregates. Besides, TA-HEVs could be present in DC- and T-cell-rich regions, as well as in B-cell-rich areas (6, 30). Wang et al. demonstrated that the rapid generation of synthetic human HEV-like structures by a tissue-bioengineering approach effectively enabled the formation of lymphoid structures with TLS functional properties in vivo, which acted as lymphatic hubs facilitating T cell infiltration into the TME and eliminate tumor cells (31). Mature HEVs, rather than lymphatics or blood vessels, have been shown to mediate CD8⁺ T cell infiltration, whereas the immune checkpoint ligands expressed on mature HEVs could negatively regulate CD8⁺ T cell entry into TLSs (32). There is currently still a debate to which extent TA-HEVs are necessary to actively influence cancer progression in TLSs or TLS-like structures (17). However, due to the lack of sufficient data, further assessment involving the impact of different maturation degrees and distributions of TA-HEVs on prognosis cannot be performed.

To comprehensively explore the possible factors affecting TA-HEV status in solid tumors, we assessed differences of common clinicopathological characteristics between the HEV-positive and HEV-negative patients. Our pooled results indicated that positive TAHEVs were inversely associated with nodal metastasis and distant metastasis. Similar to the current study, TA-HEVs were found to be negatively related to Clark level and Breslow thickness, and positively correlated with T-cell infiltration in primary melanomas (33). A higher density of TA-HEVs was observed in microsatellite-unstable colorectal carcinomas compared to microsatellite-stable tumors (25). Furthermore, HEV-high gastric tumors exhibited increased immune-modulating chemokines, activated pathway of type I or II interferon, and upregulated immune checkpoints such as PD-1 and TIGIT (21). These links might suggest that induction of TA-HEVs was most pronounced during the initial stages of tumor development when the immune response was expected to be the highest. Consequently, the presence of TA-HEVs might be a good proxy to assess the strength of ongoing anti-tumor immune responses. However, regarding sex, LVI, clinical stage, and depth of invasion, no significant difference was observed between HEV-positive and HEV-negative patients. Additionally, we discovered a positive correlation between TA-HEVs and worse tumor differentiation. One possible explanation was that poorly differentiated tumor cells tended to trigger early immune responses within the tumor, resulting in increased production of TA-HEVs, and facilitating immune cell infiltration into the TME (22). However, further studies are required to fully explore underlying mechanisms involved in this process.

Given these results, TA-HEV-inducing strategies may represent an exciting prospect for future cancer immunotherapy. Although our study revealed that TA-HEVs could act as valuable prognostic biomarkers in solid tumors, the results should be interpreted with caution. First, the cut-off values for TA-HEVs among the included studies were inconsistent, which might affect the evaluation of their clinical value. Second, the HRs and 95% CIs of some included articles were indirectly extracted from KM curves, which were less reliable than those directly obtained from original articles. Third, the number of included studies was limited, and all had small sample sizes and were retrospective. Moreover, treatment options varied significantly across different cancer types, which might influence the predictive value of TA-HEVs.

Overall, this is the first comprehensive analysis to explore the prognostic value of TA-HEVs and determine their relationships with clinicopathological features in solid tumors based on existing literature. Despite the aforementioned limitations, our results demonstrated that TA-HEVs might serve as new immune-related biomarkers for clinical assessments and prognosis prediction in solid tumors, providing clinical basses for cancer individualized treatment. However, further exploration with a larger sample size and a unified detection method is required to assess potential effects of TA-HEVs on different solid tumors.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

BW: Conceptualization, Software, Validation, Writing – original draft, Writing – review & editing. YH: Formal analysis, Investigation, Methodology, Writing – review & editing. JL: Formal analysis, Funding acquisition, Writing – original draft. XZ: Resources, Visualization, Writing – review & editing. YD: Resources, Software, Writing – review & editing. YJ: Funding acquisition, Visualization, Writing – review & editing.