Single-nucleus RNA sequencing of 189 tumors identifies age-linked shifts in colorectal cancer microenvironment composition

Dana-Farber, Mass General Brigham Gene Lay Institute, and Broad Institute researchers performed single-nucleus RNA sequencing on 189 archived tumors, generating profiles for more than 850,000 cells. They modeled age as a continuous variable rather than a binary cutoff, controlling for tumor site, stage, sex, and prior therapy. This approach detected gradual increases in fibroblast and stromal gene programs and decreases in T-cell and myeloid signatures that became detectable below age 50.

American Cancer Society incidence data show a 2.9 percent annual rise in colorectal cancer diagnoses under age 50 from 2013 to 2022, with the disease now the leading cancer killer in that cohort. The sequencing results align with clinical observations of later-stage presentation and poorer outcomes in younger adults. The cellular patterns suggest that early-onset tumors may evade immune surveillance more effectively than later-onset disease.

Operationally the map supplies candidate targets for age-stratified trials. Agents modulating stromal signaling or restoring T-cell recruitment can now be tested first in the subgroup showing the strongest deviation from older-patient baselines. Biobanks holding frozen specimens with linked clinical data become priority resources for validating these signatures prospectively.

Follow-on studies will quantify whether the observed stromal enrichment exceeds 15 percent in independent cohorts and whether it correlates with progression-free survival differences within 36 months of diagnosis.