Activating a B cell immune response regresses immunologically cold tumours PMID: 42286216

ADC Targets in Oncology

2026-04-10

Activating a B cell immune response regresses immunologically cold tumours

Nat Nanotechnol. 2026 Jun;21(6):892-903. doi: 10.1038/s41565-026-02170-9.

Heena Aggarwal ^# ¹ ² ³ , Nimish Gupta ^# ⁴ , Aniruddha Sengupta ^# ⁴ ⁵ , Arindam Sarkar ^# ⁴ , Sanghamitra Mylavarapu ^# ⁴ , Ivan S Pires ¹ , Tanmoy Saha ¹ , Binayak Sarkar ¹ , Ashish Kulkarni ⁶ , Vinay S Mahajan ¹ , Lipika Goyal ⁷ , Aditya Bardia ⁸ ⁹ , Richard Fahrner ⁸ , Ermanno Gherardi ⁸ ¹⁰ , Raghunath Mashelkar ⁸ , Patrick Soon-Shiong ⁸ , Hae Lin Jang ¹¹ ¹² ¹³ , Shiladitya Sengupta ¹⁴ ¹⁵ ¹⁶

Affiliations

1. Center for Engineered Therapeutics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA.
2. Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
3. Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
4. Akamara Therapeutics Inc, New Delhi, India.
5. Sun Pharma Advanced Research Company Limited, Vadodara, India.
6. University of Massachusetts, Amherst, MA, USA.
7. Stanford Cancer Center, Stanford, CA, USA.
8. Alyssum Therapeutics Inc, Cambridge, MA, USA.
9. Department of Medicine, Division of Hematology/Oncology, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
10. University of Pavia, Pavia, Italy.
11. Center for Engineered Therapeutics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA. [email protected].
12. Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
13. Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
14. Center for Engineered Therapeutics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA. [email protected].
15. Alyssum Therapeutics Inc, Cambridge, MA, USA. [email protected].
16. Harvard Cancer Consortium, Boston, MA, USA. [email protected].
# Contributed equally.

Abstract

Progress in immuno-oncology has been stymied by poorly immunogenic 'cold' tumours and the focus on T cells at the cost of Other immune cells. Here we report that AT-1965, a small molecule in a lipid nanoparticle, induces rapid regression of poorly immunogenic tumours with the formation of immune memory through interaction with Cap-specific RNA (nucleoside-2'-O-)-methyltransferase 2 (CMTR2) in Cancer cells, triggering an innate inflammatory viral defence response. AT-1965-treated tumours were found to be highly infiltrated with B cells, which are known to act as early responders to viral signatures. Genetic knockout of functional B cells abrogated the anti-tumour efficacy of AT-1965, directly implicating B cells in the anti-tumour outcome. Our results rationalize clinical data showing that patients with high CMTR2 expression in tumours have a poor prognosis and that B cell infiltration is associated with long-term survival in multiple tumour types. The AT-1965 nanomedicine-inspired discovery of CMTR2 as a potential Cancer target and B cell recruitment opens a new frontier for immuno-oncology.