Exploiting the CXCR3/CXCL10 axis overrides tumor immune suppression by enhancing immune trafficking and effector cell priming in HNSCC

Sep 22, 2026

Immune-suppressive tumor microenvironments restrict the infiltration and activation of CD8+ T, CD4+ T, and NK cells, limiting checkpoint blockade efficacy. Using murine head and neck squamous cell carcinoma models, intratumoral CXCL10 delivery drove tumor elimination and suppressed recurrence. CXCL10 recruited cytotoxic lymphocytes while enhancing their antitumoral functions, activation, antigen specificity, and reducing T cell exhaustion, alongside stunting angiogenesis. Enhanced presence and proliferation in tumor-draining lymph nodes supported T cell priming and trafficking, and combined IT-CXCL10 plus anti-PD-1 improved tumor clearance by lowering barriers to effective checkpoint blockade.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Overview

Intratumoral CXCL10 enhances antitumor immunity

CXCR3/CXCL10 axis and checkpoint blockade synergy

Implications for immunotherapy

RESEARCH ARTICLE IMMUNOLOGY AND INFLAMMATION OPEN ACCESS Exploiting the CXCR3/CXCL10 axis overrides tumor immune suppression by enhancing immune trafﬁcking and effector cell priming in HNSCC Cheyanne K. Shinna,b,c , Robert Saddawi-Konefkac,d,e , Catherina L. Salangaa,b, Shiruyeh Schokrpurc , J. Silvio Gutkindb,c,1, and Tracy M. Handela,b,1 Affiliations are included on p. 11. Edited by Jason G. Cyster, University of California San Francisco, San Francisco, CA; received August 18, 2025; accepted July 9, 2026 Immune-suppressive tumor microenvironments (TMEs) limit the impact ofcheckpoint blockade in many cancers by restricting the inﬁltration and activation of CD8+ T, CD4+ T, and NK cells. Utilizing murine models of head and neck squamous cell carcinoma, we demonstrated that intratumoral (IT) delivery of CXCL10 drives tumor elimination and inhibits recurrence not only by recruiting these cells but by enhancing their antitumoral functions and stunting angiogenesis. CD8+ T cells also display enhanced activation, tumor-antigen speciﬁcity, and decreased T cell exhaustion. Despite administration of CXCL10 into tumors, CD8+ and CD4+ T cells show enhanced presence and proliferation in tumor-draining lymph nodes (TdLNs), consistent with T cell priming and traﬃcking between tumors and TdLNs. Together, the data suggest that CXCL10 promotes a mutually reinforcing feedback loop that reprograms the TME toward an immunologically responsive antitumoral state. Combining IT-CXCL10 and anti-PD-1 further increased tumor clearance, indicating that CXCL10-driven reprogramming of the TME lowers barriers to eﬀective checkpoint blockade. CXCR3 | CXCL10 | tumor microenvironment | immune trafficking | immunotherapy Immunotherapy with immune checkpoint blockade agents (ICBs) such as pembroli zumab and nivolumab has revolutionized cancer treatment by leveraging the host immune system to eliminate cancer ( 1) . These ICBs prevent PD-1/PD-L1 signaling from blocking the cytotoxic function ofT cells and accelerating CD8+ T cell exhaustion (2, 3) . However, favorable objective response rates are limited to only 10 to 40% of cancer patients (4–7) . The failure of these ICBs, as well as standard treatments, is due in part to the ability of resistant tumors to limit the infiltration and activation of cytotoxic CD8+ T and NK cells (8, 9) . CD8+ T and NK cells release apoptosis-inducing cytotoxins (perforin and granzyme), as well as proinflammatory cytokines [interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) to eliminate cancer, and are essential for effective responses to immunotherapy. Accordingly, the abundance of cytotoxic cells within tumor tissue following various treatments is associated with a positive prognosis in several cancers ( 10, 11) . However, exclusion of these cells from tumors can result from physical barriers ( 12), immunosuppressive signaling (13), and dysfunctional vasculature ( 14) . Further, the mere infiltration of cytotoxic cells into the tumor microenvironment (TME) does not guarantee positive outcomes. Immunosuppressive cytokines and chronic antigen stimulation can lead to the dysfunction of these cells, limiting their ability to control tumor growth (15). Additionally, the exclusion of dendritic cells (DCs) contributes to immune suppression by stunting the generation of T cells primed to tumor-specific antigens (TSAs) ( 16, 17) . To broaden the success of immunotherapy, approaches are needed that override immune suppression and promote the generation and maintenance ofTSA-reactive T cells. The chemokine receptor CXCR3 is a key regulator of cytotoxic immune cell responses within solid tumors ( 18, 19) . It responds to IFN-inducible ligands CXCL9, 10, and 11, and controls the migration, spatial distribution, and function of activated T and NK cells ( 18) . CXCL9 and 10 are important for the antitumoral functions of CD8+ T cells, type-1 helper (Th1) CD4+ T cells, and NK cells (20), and reduced expression

FAQs

How does intratumoral CXCL10 affect tumor growth and recurrence?

Intratumoral CXCL10 delivery suppressed tumor growth and recurrence in murine head and neck squamous cell carcinoma models by driving tumor elimination.

What immune changes are induced by CXCL10 in the tumor microenvironment and lymph nodes?

CXCL10 increased recruitment, activation, and proliferation of CD8+ T, CD4+ T, and NK cells, including enhanced presence and proliferation in tumor-draining lymph nodes consistent with priming and trafficking.

Why does combining CXCL10 with anti-PD-1 improve treatment outcomes?

The data indicate CXCL10 reprograms the tumor microenvironment into an immunologically responsive antitumoral state, lowering barriers to effective checkpoint blockade and increasing tumor clearance with anti-PD-1.

Sep 22, 2026

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