Spatial predictors of response to chemo-immunotherapy in microsatellite stable metastatic colorectal cancer
Microsatellite-stable (MSS) colorectal cancers (CRC) are largely unresponsive to immune checkpoint inhibition (ICI). The MAYA trial used temozolomide (TMZ) in MGMT-silenced MSS mCRC, hypothesizing that TMZ-induced hypermutation could sensitize tumors to ICI; the primary endpoint was met, showing durable responses with TMZ plus ipilimumab and nivolumab. We perform integrated spatial, transcriptomic, and immune profiling of longitudinal tumor and blood samples from patients treated on the MAYA trial. Post-TMZ increases in tumor mutational burden associate with improved progression-free survival. Spatial profiling demonstrates that clinical benefit is greatest in permissive tumor microenvironments. Responders exhibit enrichment of cytotoxic T cells across tumor and stromal compartments, whereas non-responders display heterogeneous cellular neighborhoods, with fibroblasts in close spatial proximity to T cells, consistent with barriers to immune-mediated clearance. Longitudinal peripheral immune profiling shows that early upregulation of TIGIT and PD-1 following TMZ exposure predicts resistance. Together, these findings indicate that both mutational evolution and spatial immune architecture contribute to immune sensitization in MGMT-silenced MSS CRC. Clinical Trial Identification: NCT03832621.
Authors
- Sruthi Ranganathan (ORCID: https://orcid.org/0009-0003-0684-4263)
- Ryan Yong Kiat Tay (ORCID: https://orcid.org/0000-0002-9773-411X)
- Subhra K. Biswas
- Elisa Scarselli (ORCID: https://orcid.org/0000-0002-5393-6713)
- Mai Chan Lau (ORCID: https://orcid.org/0000-0002-7698-4697)
- Alessandra Raimondi (ORCID: https://orcid.org/0000-0002-8999-2899)
- Elisa Micarelli (ORCID: https://orcid.org/0000-0002-1180-0359)
- Akhila Balachander (ORCID: https://orcid.org/0000-0002-2168-0063)
- Felicia Wee (ORCID: https://orcid.org/0009-0004-7624-3751)
- Joseph Jonathan Zhao (ORCID: https://orcid.org/0000-0002-2002-5390)
- Jia-Ying Joey Lee (ORCID: https://orcid.org/0000-0002-0420-7098)
- C. Damonte (ORCID: https://orcid.org/0000-0003-0565-0478)
- Jeffrey Chun Tatt Lim (ORCID: https://orcid.org/0000-0002-8903-8843)
- Paolo Manca (ORCID: https://orcid.org/0000-0002-3813-6339)
- Lit‐Hsin Loo (ORCID: https://orcid.org/0000-0001-6303-9840)
- Zhen Wei Neo (ORCID: https://orcid.org/0009-0005-8520-7936)
- Sara Lonardi (ORCID: https://orcid.org/0000-0002-7593-8138)
- Raghav Sundar (ORCID: https://orcid.org/0000-0001-9423-1368)
- Guido Leoni (ORCID: https://orcid.org/0000-0003-0502-1962)
- Khi Yung Fong (ORCID: https://orcid.org/0000-0001-8194-0800)
- David S.P. Tan (ORCID: https://orcid.org/0000-0001-9087-5262)
- Willa Wen‐You Yim (ORCID: https://orcid.org/0000-0003-0223-6212)
- You Yi Hwang (ORCID: https://orcid.org/0000-0001-7490-2507)
- Giovanni Randon (ORCID: https://orcid.org/0000-0003-0244-445X)
- Laurent Rénia (ORCID: https://orcid.org/0000-0003-0349-1557)
- Hui Xian Chin
- Craig Ryan Joseph (ORCID: https://orcid.org/0009-0004-5326-9692)
- Filippo Pietrantonio (ORCID: https://orcid.org/0000-0002-8530-8420)
- Chiara Cremolini (ORCID: https://orcid.org/0000-0002-0520-4841)
- Crystal Tze Ying Tan (ORCID: https://orcid.org/0000-0003-4916-0657)
- Joe Poh-Sheng Yeong (ORCID: https://orcid.org/0000-0002-6674-7153)
- Chong Boon Teo (ORCID: https://orcid.org/0000-0002-4388-2766)
- Li Yen Chong (ORCID: https://orcid.org/0000-0002-4623-4633)
- Joan Choo
- Kexin Zhu (ORCID: https://orcid.org/0000-0001-7173-6881)
- Federica Marmorino
- Michele Prisciandaro
- Federica Morano
- Diana GS Lim
Institutions
- Agency for Science, Technology and Research (SG)
- National University of Singapore (SG)
- Nanyang Technological University (SG)
- Medical University of Graz (AT)
- University of Cambridge (GB)
- Singapore Immunology Network (SG)
- Yale Cancer Center (US)
- Yale University (US)
- National University Cancer Institute, Singapore (SG)
- Istituto Oncologico Veneto (IT)
- Duke-NUS Medical School (SG)
- Nouscom (Italy) (IT)
- National University Health System (SG)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Azienda Ospedaliera Universitaria Pisana (IT)
- Institute of Molecular and Cell Biology (SG)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-25
- DOI
- https://doi.org/10.1038/s41467-026-72204-2
- Primary Topic
- Genetic factors in colorectal cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00