RE: An immunosuppressive tertiary lymphoid structure is associated with adverse prognosis in gastric-type endocervical adenocarcinoma

To the Editor, We read with great interest the study by Xu et al.,1 which provides a comprehensive characterization of the tumor immune microenvironment (TIME) in gastric-type endocervical adenocarcinoma (GAC). The authors describe a distinct “immune-cold” landscape characterized by scarce cytotoxic T cells, abundant M2-polarized macrophages, and immunosuppressive tertiary lymphoid structures (TLS) associated with poor prognosis. Although we commend the authors for challenging the paradigm that TLS are universally beneficial, we believe two critical mechanistic factors warrant further discussion to contextualize these findings. First, the immune phenotype described in GAC (T-cell exclusion, neutrophil/macrophage enrichment) bears a striking resemblance to the immune landscape driven by STK11/LKB1 loss, a phenomenon well-established in other adenocarcinomas.2 Given that STK11 mutations are highly prevalent in GAC,3 it is plausible that the immunosuppressive milieu and “dysfunctional” TLS are downstream consequences of STK11 loss rather than independent stochastic events. STK11 deficiency is known to silence the STING pathway and promote the recruitment of suppressive myeloid cells, which physically exclude T cells from tumor nests.2 Integrating STK11 status into future analyses could reveal whether the adverse prognosis is driven by the TLS itself or by the aggressive genomic genotype that sculpts this hostile microenvironment. Second, we urge caution regarding the classification of PD-1-negative CD8+ T cells within TLS as “bystanders” with limited antitumor function. In mucosal malignancies such as cervical cancer, tumor-specific immunity is often mediated by CD103+ tissue-resident memory T cells (Trm).4 Crucially, functional Trm populations can exhibit variable or low PD-1 expression while retaining potent cytotoxic potential upon reactivation.5 We noted that CD103 (ITGAE) was absent from the authors’ RNA-seq deconvolution and mIF panels. Without assessing CD103, it is difficult to distinguish true bystanders from bona fide Trm cells that are simply suppressed or physically sequestered by the dense M2-macrophage stroma described by the authors. This distinction has profound therapeutic implications. If these T cells are not irrelevant bystanders but rather suppressed Trm populations within an STK11-driven myeloid niche, the clinical strategy should shift from “replacing” the immune system to “unleashing” it. Therapies targeting the myeloid axis (eg, CSF1R inhibitors) to deplete the M2 barrier may be required to reinvigorate these resident T cells before checkpoint blockade can be effective. Rashad Ismayilov (Conceptualization, Formal analysis, Investigation, Writing—original draft) and Ozden Altundag (Conceptualization, Supervision, Writing—original draft, Writing—review & editing) No funding was received for this work. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article. There are no data associated with this research.