Renal cell carcinoma (RCC) is the most common subtype of kidney cancer and continues to rise in incidence worldwide. RCC is also regarded as one of the most immune- and angiogenesis-infiltrated malignancies. In recent years, immune checkpoint blockade (ICB)-based combination therapies have fundamentally reshaped the treatment paradigm for advanced RCC, heralding a shift from monotherapy with targeted agents to an era of immunotherapy–targeted therapy combinations. As immunotherapy continues to transform RCC management, overcoming treatment resistance has become a pressing clinical challenge. Tumors adopt various immune escape mechanisms to evade immune recognition and destruction, ultimately leading to ICB failure. Therefore, elucidating the cellular subsets and molecular pathways associated with immunotherapy response is essential for discovering strategies to overcome resistance and enhance therapeutic efficacy.
Study Overview
A research team led by Prof. Xinan Sheng from the Department of Urologic Oncology, Peking University Cancer Hospital, recently published a study in Advanced Science titled “MARCO⁺ Tumor-Associated Macrophages Impede CD8⁺ T Cell Immunity to Facilitate Immunotherapy Resistance in Renal Cell Carcinoma.”
The study identifies a crucial role for MARCO⁺ tumor-associated macrophages (TAMs) in driving immunotherapy resistance in RCC. The team demonstrates that MARCO⁺ TAMs suppress CD8⁺ T cell activation by interfering with MHC-I–mediated antigen presentation. Mechanistically, MARCO upregulates SOCS1, which inhibits JAK1 kinase activity and disrupts the JAK1–STAT1–NLRC5 signaling cascade, resulting in reduced MHC-I expression.
This work reveals a previously unrecognized immune escape mechanism within the RCC tumor microenvironment and provides a theoretical basis and therapeutic rationale for developing agents that sensitize tumors to immunotherapy.
Key Findings
1. Single-cell analysis identifies tumor microenvironment signatures associated with ICB response in RCC
Immune-resistant tumors exhibit a distinct immunosuppressive niche characterized by:
- Selective enrichment of MARCO⁺ TAMs, and
- Marked impairment of CD8⁺ cytotoxic T lymphocyte (CTL) effector functions.
2. MARCO⁺ TAMs from RCC suppress CD8⁺ T-cell activation and weaken antitumor immunity
Multicellular in vitro co-culture experiments revealed that RCC-derived MARCO⁺ TAMs express high levels of immunosuppressive molecules and signatures. These macrophages inhibit CD8⁺ T-cell proliferation and effector cytokine production, thereby diminishing T-cell–mediated tumor killing. Importantly, blocking MARCO reversed the suppressive effect of TAMs on CD8⁺ T-cell cytotoxicity.
3. Mechanistic insights: an immune escape program driven by the JAK1–STAT1–NLRC5 axis
Through transcriptomic profiling and molecular assays, the researchers showed:
- MARCO upregulates SOCS1,
- SOCS1 inhibits JAK1 kinase activity,
- Resulting in disrupted JAK1–STAT1–NLRC5 signaling,
- Leading to reduced MHC-I expression and diminished antigen presentation capacity of TAMs.
This mechanistic axis highlights a MARCO–SOCS1–mediated immune escape pathway within the RCC tumor microenvironment.
4. Therapeutic potential of targeting MARCO
In animal models, blockade of MARCO significantly enhanced systemic immune responses and improved the antitumor efficacy of anti–PD-1 therapy. These findings position MARCO as a promising therapeutic target for restoring immune recognition in immunotherapy-resistant RCC patients.
Authorship and Funding
Prof. Xinan Sheng and Associate Researcher Xiaowen Wu from Peking University Cancer Hospital served as co-corresponding authors. Dr. Jiayuan Chen is the first author of this study.
The work was supported by grants from:
- The National Natural Science Foundation of China,
- The Ministry of Education Chunhui Program,
- The Beijing Natural Science Foundation, and others.
Article Information
Title: MARCO⁺ tumor-associated macrophages impede CD8⁺ T cell immunity to facilitate immunotherapy resistance in renal cell carcinoma Authors: Jiayuan Chen, Jiazhi Mo, Jinchang Wei, Mengnan Qu, Jie Dai, Yan Kong, Huayan Xu, Juan Li, Xieqiao Yan, Chuanliang Cui, Lu Si, Zhihong Chi, Jun Guo, Xiaowen Wu*, Xinan Sheng* Journal: Advanced Science DOI: 10.1002/advs.202514600
About the Journal
Advanced Science is an interdisciplinary, fully open-access journal within Wiley’s flagship Advanced series. It publishes cutting-edge basic and applied research spanning materials science, physics, chemistry, medicine, life sciences, environmental science, engineering, and social sciences. The journal aims to broaden access to scientific innovation through open dissemination.
The 2024 Journal Impact Factor (JIF) is 14.1, with a five-year JIF of 15.6, a JCI of 1.90, and a CiteScore of 18.2. In the 2025 Chinese Academy of Sciences journal ranking, Advanced Science is classified as a Category 1, Top-tier comprehensive journal.
