Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, underscoring the urgent need for effective therapeutic strategies [1]. In this context, a recent study by Zeng et al. [2] provides compelling insights into the oncogenic role of transmembrane 4 L six family member 1 (TM4SF1) in HCC progression and immunotherapy resistance. By elucidating the multifaceted functions of TM4SF1, the study offers a promising avenue to enhance the current understanding of oncogenic pathway-driven immune response and shift treatment paradigms.

TM4SF1, a tumor-associated antigen implicated in multiple cancers, facilitates tumor angiogenesis, proliferation, and migration through interactions with integrins, receptor tyrosine kinases and collagens [3]. While extensively studied in epithelial malignancies, its role in HCC pathogenesis, particularly in modulating non-secretory phenotypic senescence and its impact on immune responses and immunotherapy, remains poorly understood. The current study by Zeng et al. [2] demonstrated that TM4SF1 is highly expressed across multiple human HCC datasets and its elevated expression is associated with worse overall and disease-free survival. Functional analyses revealed that TM4SF1 knockdown suppressed HCC proliferation in vitro and in vivo, primarily by inducing non-secretory senescence. This senescent state was mediated by upregulation of the tumor suppressor proteins p16 and p21. Mechanistically, TM4SF1 enhanced the interaction between AKT1 and PDPK1, promoting AKT phosphorylation and subsequently downregulating p16 and p21 (Fig. 1). These findings position TM4SF1 as a critical regulator of senescence escape in HCC, providing a rationale for targeting this molecule.

Beyond its role in cellular proliferation, the team also demonstrated that TM4SF1 significantly modulates the immune landscape of HCC [2]. Profiling of immune cells from transplanted Tm4sf1 knockdown (Tm4sf1 KD) liver tumours in immunocompetent mice showed increased granzyme-B and IFNg-expressing activated CD8 T, along with reduced PD-1+ exhausted CD8 T cells, indicative of enhanced anti-tumour immunity. Furthermore, TM4SF1-mediated AKT phosphorylation upregulated PD-L1 expression while simultaneously reducing MHC I antigen presentation molecule levels on tumor cells (Fig. 1). This finding is consistent with previous reports in bladder and lung cancers linking AKT phosphorylation to PD-L1 and MHC I regulation [4,5]. The dual modulation of impaired CD8 T cell cytotoxicity and the increased proportion of exhausted CD8 T cells contributes to an immunosuppressive tumor microenvironment.

Next, the team validated the therapeutic potential of targeting TM4SF1 using an adeno-associated virus (AAV)- mediated approach in vivo [2]. In preclinical models, AAV-mediated shRNA knock down of Tm4sf1 in murine liver cancer tissues induced tumor senescence, reduced tumor burden, and synergistically enhanced the efficacy of anti-PD-1 therapy. The combination of targeting TM4SF1 and PD-1 enhanced cytotoxic function while reduced exhaustion status of the tumour-infiltrating CD8 T cells. These findings highlight TM4SF1 as a pivotal target to overcome key barriers to successful immunotherapy in HCC by reactivating anti-tumor immunity and inducing tumor cell senescence. Clinical data further supported this, revealing that lower TM4SF1 expression corresponded with higher levels of active CD8 T cells, lower PD-L1 expression and improved outcomes in 14 HCC patients undergoing radical resection followed by anti-PD-1 immunotherapy, where relapse serving as a criterion to assess response.

The findings presented by Zeng et al underscore the critical dual role of TM4SF1 in both directly inhibiting senescence of tumour cells and shaping an immunosuppressive tumor microenvironment that contributes to resistance to immunotherapy in HCC [2]. The link between senescence, immune modulation and immunotherapy response was previously established in the HCC preclinical model [6] and extensively discussed as a potential onco-therapeutic target for treating human cancers [7]. For example, it has been shown that the chemotaxis of immunosuppressive myeloid cells induced by pre-malignant senescent hepatocytes enables evasion from immunosurveillance and promotes HCC development [8]. Building on these insights, future efforts should focus on translating the preclinical success of TM4SF1-targeted strategies into clinical applications. Despite recent advancements in immunotherapies for advanced HCC, objective response rate remains modest [9]. Therefore the integration of TM4SF1 inhibitors with immune checkpoint blockade offers a promising therapeutic avenue, particularly for patients with limited responses to current immunotherapies. Further exploration of the molecular underpinnings of TM4SF1-mediated immune modulation across diverse HCC subtypes may uncover novel biomarkers to stratify patients and predict therapeutic outcomes. Leveraging advanced technologies like single-cell transcriptomics and spatial proteomics, future studies can delineate TM4SF1’s context-specific roles within the immune-tumor ecosystem, paving the way for precision immunotherapy approaches. Ultimately, targeting TM4SF1 holds the potential to overcome key hurdles in immunotherapy, offering a novel therapeutic option for patients with advanced HCC. However, due to the significantly high inter-and intra-genomic heterogeneity in HCC [10], targeting TM4SF1 may yield inconsistent response across tumours and patients. Additionally, issues related to toxicity and resistance will require careful evaluation. Insights from ongoing clinical trials targeting AKT, the key downstream target of TM4SF1, in HCC will provide valuable perspectives for addressing these challenges [11].

In conclusion, this study highlights the pivotal role of TM4SF1 in HCC progression and its contribution to the immunosuppressive microenvironment. Targeting TM4SF1 holds promise for overcoming immunotherapy resistance and improving patient outcomes. These findings not only identify TM4SF1 as a novel therapeutic target but also underscore the importance of integrating molecular and immune-based strategies to enhance the efficacy of cancer treatment.