Abstract Perineural invasion (PNI) is a common pathologic feature associated with poor prognosis in colorectal cancer. A better understanding of the mechanisms underlying PNI formation could help identify potential strategies to inhibit tumor progression. In this study, we revealed an integral role of CD4+ T cells in the development and progression of PNI in colorectal cancer. Single-cell RNA sequencing, spatial transcriptomics, and multiplex IHC profiling uncovered a distinct HSPA6+ CD4+ T-cell subset expressing T stress (Tstr) cell markers in colorectal cancer PNI tissues. Schwann cells (SC) colocalized with the HSPA6+ CD4+ Tstr cells in PNI, and functional studies showed that SCs promoted Tstr cell differentiation, whereas Tstr cells enhanced SC migration. Interaction between SCs and CD4+ T cells activated the mitogen-activated protein kinase (MAPK) pathway in SCs and the JAK–STAT pathway in Tstr cells, and inhibition of MAPK and STAT signaling suppressed nerve invasion of colorectal cancer cells in vivo. Moreover, SCs in contact with tumor cells possessed the ability to recruit CD4+ T cells; tumor-derived TNFα stimulated SCs to secrete CCL4, thereby recruiting CD4+ T cells toward SCs. The anti-TNFα mAb infliximab reversed the proinvasive and promigratory effects of SCs on colorectal cancer cells and reduced intratumoral CD4+ Tstr cells, and the combination of infliximab with anti–PD-1 treatment produced a combinatorial tumor-suppressive effect. Together, this study suggests that SCs near colorectal cancer tissues recruit CD4+ T cells and promote their conversion to CD4+ Tstr cells to establish an immunosuppressive microenvironment and simultaneously enhance the migration and tumor-promoting capabilities of SCs, thereby accelerating PNI development. Significance: A CD4+ T cell subtype forms a feedback loop with Schwann cells that promotes perineural invasion in colorectal cancer and can be targeted to suppress tumor progression and enhance PD-1 blockade efficacy.
Abstract Although chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant efficacy in treating hematologic malignancies, its application in solid tumors remains challenging. A major limitation of CAR T-cell efficacy in solid tumors is the functional exhaustion of CD8+ T cells. In this study, we investigated metabolic regulators of CD8+ T-cell exhaustion, identifying that cystine promotes CD8+ T-cell exhaustion. RNA sequencing (RNA-seq) analysis of an in vitro exhaustion model revealed that SLC7A11 was significantly upregulated in exhausted CD8+ T cells. A monoclonal antibody specifically targeting SLC7A11 was subsequently generated, and its binding affinity was rigorously validated. Single-cell RNA-seq and functional studies demonstrated that inhibition of SLC7A11 promoted the expansion of CD8+ stem-like memory T cells and alleviated T-cell exhaustion. In vivo, treatment with the anti-SLC7A11 antibody enhanced the antitumor efficacy of CAR T cells. Mechanistically, SLC7A11 inhibition suppressed cystine uptake, which activated the GCN2–eIF2α–SLC1A5 signaling axis. Upregulation of SLC1A5 increased glutamine uptake to stimulate oxidative phosphorylation and support mitochondrial fitness. Together, these findings demonstrate that cystine restriction alleviates CD8+ T-cell exhaustion and enhances the efficacy of CAR T-cell therapy. Significance: Inhibition of SLC7A11-mediated cystine uptake improves the anti-tumor activity of CD8+ CAR-T cells by activating the GCN2-eIF2α-SLC1A5 axis to promote oxidative phosphorylation and mitochondrial fitness, overcoming T cell exhaustion.
Fungi have been detected within human tumors and shown to support tumor progression. A better understanding of how intratumoral fungi evade innate immunity, remodel the tumor microenvironment (TME), and promote tumorigenesis may provide insights into cancer pathogenesis and therapeutic strategies. Here, we showed that aggressive human head and neck squamous cell carcinomas (HNSCCs) harbor an elevated fungal burden, including the environmental fungus Cladosporium cladosporioides, and are infiltrated by IL1B-high neutrophils with impaired reactive oxygen species (ROS) production and phagocytosis, as well as IL1B-high macrophages. In a mouse model in which Ikka ablation drives tumorigenesis through EGFR and STAT3 activation, oral C. cladosporioides infection recapitulated key features of the human HNSCC TME, elevated serum IL-1β and IL-17A levels, and promoted both oral and skin SCC development. Oral fungal infection also increased the acidic metabolites uric acid and lactate in the TME. These metabolites enhanced C. cladosporioides-induced IL-1β production while reducing ROS production in neutrophils, thereby impairing fungal clearance. Mechanistically, C. cladosporioides, IL-1β, and IL-17A activated STAT3 and cyclin D1 signaling in SCC cells. Epithelial Stat3 deletion abrogated both Ikka loss-driven and fungus-enhanced oral and skin carcinogenesis, reduced macrophage accumulation, restored normal oral neutrophil phenotypes, and cleared oral fungal infection. Furthermore, IL-1β induced by C. cladosporioides inoculation drove systemic inflammation that promoted skin SCC via an IL-1β/IL-1R feedback loop involving neutrophils and macrophages. Together, these findings identify a fungus-driven immunosuppressive circuit in which tumor-derived acidic metabolites impair antifungal immunity, thereby promoting both local and distal SCC progression.
Receptor tyrosine kinases (RTKs) classically function as oncogenic drivers that promote survival and proliferation upon ligand binding. A subset of RTKs can also function as dependence receptors, inducing apoptosis in the absence of their ligands. Genetic alterations that enhance RTK signaling are well characterized in cancer and can be targeted with kinase inhibitors, which show limited efficacy in some clinical settings. Elucidation of whether oncogenic mutations can promote tumorigenesis by directly abolishing the pro-apoptotic activity of dependence receptors could help improve strategies to target RTKs. Here, we identified MET exon 14 skipping (METex14Del) as a paradigmatic example of an oncogenic alteration that drives tumorigenesis through genetic inactivation of the dependence receptor function of an RTK. METex14Del removed both the caspase cleavage site and adjacent CBL-binding motif, preventing generation of the pro-apoptotic p40MET fragment while sustaining oncogenic MET signaling. Uncoupling regulatory functions of MET using genome editing showed that loss of apoptosis capacity is a critical determinant of METex14Del-driven tumorigenesis. Combined-but not individual-mutation of the caspase and CBL sites was sufficient to recapitulate resistance to apoptosis and tumor growth induced by METex14Del in HGF-humanized mouse models. Importantly, inducible re-expression of p40MET in METex14Del-expressing cells restored apoptotic sensitivity, decreased tumor formation in vivo, and resensitized tumors to capmatinib. Together, these findings redefine RTKs as receptors with dual oncogenic and tumor-suppressive functions and show that disruption of dependence receptor-mediated apoptosis is an oncogenic mechanism. These results provide a conceptual framework explaining why therapies targeting only RTK signaling may fail and support strategies restoring dependence receptor function to achieve durable tumor suppression.
Aberrant extracellular matrix (ECM) remodeling in tumors is characterized by altered deposition, enzymatic cross-linking, degradation, and organization of matrix molecules that in turn can contribute directly to tumor invasiveness, immune evasion, and resistance to therapy. Traditionally, cancer-associated fibroblasts (CAFs) have been considered the principal architects of ECM remodeling in tumors. However, the role of non-fibroblast cell populations in modulating ECM structure and function and how these processes intersect with immune regulation, metabolism, and metastasis is also crucial but currently underappreciated. Challenging the prevailing fibroblast-centric paradigm, this review provides an overview of how non-fibroblast cell types engage in dynamic crosstalk and collectively shape the biochemical and biomechanical landscape of tumors. Therapeutic strategies targeting these alternative stromal players could disrupt pro-tumor ECM dynamics, enhance anti-tumor immunity, and restore tissue homeostasis. Thus, a comprehensive understanding of the intricate network of non-fibroblast stromal cells within the tumor microenvironment (TME) can help elucidate opportunities for precision medicine and personalized cancer care, leading to the development of innovative therapeutic interventions targeting the TME.
