Immune Cell Resident Gene RBPJ Emerges as Key to Lung Cancer Immunotherapy Success

Immune checkpoint blockade has transformed the treatment landscape for non-small cell lung cancer, yet a stubborn majority of patients still fail to respond to anti-PD-1 and anti-PD-L1 therapies. A new study published in Cancer Immunology, Immunotherapy offers a detailed explanation for why some tumors surrender to these drugs while others resist them, and it points to an unexpected molecular conductor: the transcription factor RBPJ. By dissecting the single-cell architecture of lung tumors, a team of Chinese researchers has shown that a specialized population of CD8+ tissue-resident memory T cells, governed in part by RBPJ, sits at the heart of successful immunotherapy responses. The findings, released as an open-access article with a permanent DOI, could reshape how clinicians predict which patients will benefit from checkpoint inhibitors and how researchers design the next generation of immunotherapies.

Tissue-resident memory T cells, abbreviated Trm, are immune sentinels that take up permanent residence within tissues rather than circulating through the bloodstream. In epithelial barriers such as the lung, these cells act as a first line of defense, poised to recognize and attack threats at the exact site where they appear. In cancer, their role has been increasingly appreciated: tumors infiltrated by abundant CD8+ Trm cells often carry a better prognosis, and these cells are thought to be among the most important mediators of the local antitumor immune response. What has remained murky, however, is the functional diversity within the Trm compartment and precisely how these cells influence the outcome of immune checkpoint blockade, the class of therapies that unleash T cells by blocking the PD-1/PD-L1 inhibitory axis.

To resolve these questions, the research team, led by first authors Gaoming Liao, Qi Liu, and Min Zhang and corresponding authors Gaoming Liao, Jian Shi, and Xionghai Qin, assembled an unusually comprehensive analytical framework. They combined single-cell RNA sequencing, which profiles gene expression in individual cells, with single-cell T-cell receptor sequencing, which tracks the clonal lineage relationships among T cells. On top of this, they integrated large-scale bulk omics datasets drawn from public resources, including The Cancer Genome Atlas, allowing them to connect what they saw at the single-cell level with clinical outcomes across large patient cohorts. The study was conducted at institutions including the State Key Laboratory of Respiratory Disease at The First Hospital of Guangzhou Medical University, with computational support from the Guangzhou Medical University core facility, and was funded by the National Natural Science Foundation of China and several provincial research foundations.

The single-cell analysis revealed that the CD8+ Trm compartment in non-small cell lung cancer is not a monolith but a collection of at least three distinct subsets, which the researchers designated Trm-CD103, Trm-ZNF683, and Trm-NR4A1. All three expressed high levels of the canonical tissue-residency markers ITGAE, which encodes the integrin CD103, and ITGA1, which encodes CD49a, confirming their embedded status within tumor tissue. Each subset, however, was defined by its own key transcriptional regulator: ZNF683, also known as Hobit, characterized the Trm-ZNF683 population, while NR4A1, known as Nur77, marked the Trm-NR4A1 subset. Despite these differences, the subsets shared core functional features, most notably a cytotoxic program consistent with the ability to kill tumor cells directly, layered on top of the molecular machinery that anchors them in tissue.

The clinically decisive finding emerged when the researchers compared tumors from patients who responded to anti-PD-1 or anti-PD-L1 therapy with those who did not. The Trm-CD103 subset was significantly enriched in responders, and its abundance correlated with improved survival after treatment. In other words, the presence of this particular flavor of tissue-resident memory T cell, distinguished by CD103 expression, appeared to be a hallmark of tumors primed to surrender to checkpoint blockade. This observation elevates Trm-CD103 cells from a descriptive curiosity to a potential predictive biomarker: measuring their abundance, or the activity of the genes they express, could one day help oncologists identify patients likely to benefit from immunotherapy before the first infusion is given.

Lineage tracing through T-cell receptor repertoire analysis added an important layer of biological depth. The researchers found clonal expansion of Trm cells and, critically, overlap between the T-cell receptor sequences carried by Trm cells and those carried by effector and memory CD8+ T-cell subsets elsewhere in the tumor ecosystem. This shared receptor repertoire indicates that Trm cells and circulating effector cells are not isolated populations but branches of the same differentiation tree, arising from common clonal ancestors. The implication is that tissue-resident memory cells are integrated participants in the antitumor immune response rather than a separate garrison, and that a productive immune response may involve a dynamic interchange between resident and mobilized T-cell states, a process that checkpoint blockade appears to amplify.

Translating these observations into a practical tool, the team developed a core gene signature associated with Trm-CD103 cells. When applied to large-scale datasets, this signature predicted both response to anti-PD-1/PD-L1 therapy and patient prognosis, and it was associated with an immunologically active tumor microenvironment, the inflamed state in which immune cells penetrate and attack tumor tissue most effectively. A gene signature of this kind could be measured from routine tumor biopsies using standard transcriptomic assays, offering a relatively accessible route to immunotherapy response prediction that complements existing biomarkers such as tumor mutation burden and programmed death-ligand 1 expression by immunohistochemistry, neither of which is fully reliable on its own.

The mechanistic centerpiece of the study is the identification of RBPJ, a transcription factor best known for its role in Notch signaling, as a key driver of Trm proliferation. The researchers arrived at this finding through integrated single-cell analyses cross-referenced against a previously published knockout mouse experiment dataset, a strategy that allowed them to link RBPJ expression in human tumors to a functionally validated role in mouse models. According to the study, RBPJ expression was connected to enhanced efficacy of immune checkpoint blockade, with the transcription factor promoting the expansion of the CD8+ tissue-resident memory T cell pool that underpins therapeutic success. This positions RBPJ not merely as a passive marker of a favorable immune contexture but as an active lever that could, in principle, be pharmacologically manipulated to strengthen the resident T-cell response against tumors.

The therapeutic implications are considerable. If RBPJ activity or the pathways it regulates can be safely enhanced in patients, it might be possible to expand the population of CD103+ tissue-resident memory T cells within tumors and thereby convert immunologically cold or resistant lung cancers into responsive ones. Conversely, the Trm-CD103 gene signature offers an immediate near-term application as a biomarker, stratifying patients in clinical trials and guiding treatment decisions in the clinic. Both avenues will require validation in prospective studies, and the authors note that their work was conducted as an observational and computational analysis rather than an interventional trial, so the biomarker and the mechanistic hypothesis must now be tested directly in patient cohorts and experimental systems.

For a disease that remains the leading cause of cancer death worldwide, the study adds a crucial piece to the puzzle of immunotherapy heterogeneity in non-small cell lung cancer. It reframes tissue-resident memory T cells as critical mediators of antitumor immunity, promising biomarkers, and actionable therapeutic targets, all at once. The research, which was published open access on 1 October 2026 in Cancer Immunology, Immunotherapy, reflects a broader trend in cancer immunology: the move from counting immune cells in bulk toward understanding their identities, lineages, and regulatory circuits at single-cell resolution. As that resolution sharpens, the specific molecular programs that determine whether a patient’s immune system can be unleashed against their tumor are coming into focus, and RBPJ-guided CD8+ tissue-resident memory T cells now stand among the most compelling of those programs.

Subject of Research: The role of RBPJ-regulated CD8+ tissue-resident memory T cells in PD-1/PD-L1 immunotherapy response in non-small cell lung cancer

Article Title: Transcription factor RBPJ improves the efficacy of PD-1/PD-L1-based therapies in non-small cell lung cancer by expanding CD8+ tissue-resident memory T cells

Article References: Liao, G., Liu, Q., Zhang, M., Liu, Y., Li, J., Huang, S., Shi, J., & Qin, X. (2026). Transcription factor RBPJ improves the efficacy of PD-1/PD-L1-based therapies in non-small cell lung cancer by expanding CD8+ tissue-resident memory T cells. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04571-0

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04571-0

Keywords: non-small cell lung cancer, RBPJ, tissue-resident memory T cells, immune checkpoint blockade, PD-1, PD-L1, single-cell RNA sequencing, T-cell receptor, tumor microenvironment, CD103, biomarker, cancer immunotherapy