α,β-Unsaturated carbonyl functionality- those with connected carbon-carbon and carbon-oxygen double bonds- are commonly found in bioactive compounds. Late-stage functionalization of these compounds could involve oxidation of methylene (2°) C-H bonds while leaving the C-C double bonds that are important for biological activity intact1-3. Catalytic systems have been developed for selective oxidation of methylenes in the presence aromatics4 and N-heterocycles5, however olefins remain an unsolved problem. Here we show that replacing the carboxylic acid with a H-bond donor solvent in sterically hindered manganese PDP catalysts changes the active oxidant to one that accelerates electron rich methylene oxidation and significantly slows epoxidation of electron deficient olefins (kC-H[O]/kepox = 38.5). Chemoselective methylene oxidation is demonstrated in forty-five molecules housing α,β-unsaturated carbonyl functionality where all previous methods afforded allylic oxidation or epoxidation. Mechanistic studies support that the new oxidant proceeds via a more charged pathway that disfavors electron deficient bonds, demonstrating that highly reactive metal oxidants can be tuned to achieve chemoselectivity. These discoveries enable the first late-stage oxidations in complex natural products and derivatives housing these pharmacophoric substructures to furnish novel analogues and known metabolites.

Immune checkpoint blockade (ICB) has led to paradigm shifts in the treatment of various tumour types1-4, yet limited efficacy has been observed in patients with metastatic mismatch-repair proficient (pMMR) colorectal cancer5. Here we report clinical results and in-depth analysis of patients with early-stage pMMR colon cancer from the phase II NICHE study (ClinicalTrials.gov: NCT03026140). A total of 31 patients received neoadjuvant treatment of nivolumab plus ipilimumab followed by surgery. The response rate was 26% and included six patients with a major pathological response (≤10% residual viable tumour). One patient with an ongoing clinical complete response did not undergo surgery. Circulating tumour DNA (ctDNA) was positive in 26/31 patients at baseline, and clearance was observed in 5/6 responders prior to surgery, while 19/20 non-responders remained ctDNA+. Responses were observed despite a low tumour mutational burden in all tumours, while chromosomal genomic instability scores were significantly higher in responders compared to non-responders. Furthermore, responding tumours had significantly higher baseline expression of proliferation signatures and TCF1, and imaging mass cytometry revealed a higher percentage of Ki-67+ cancer and Ki-67+ CD8+ T cells in responders compared to non-responders. These results provide a comprehensive analysis of response to neoadjuvant ICB in early-stage pMMR colon cancers and identify potential biomarkers for patient selection.

Parity and breastfeeding reduce the risk of breast cancer, particularly triple-negative breast cancer (TNBC)1,2, yet the immunological mechanisms underlying this protection remain unclear. Here, we show that parity induces an accumulation of CD8+ T cells, including cells with a tissue-resident memory (TRM)-like phenotype within human normal breast tissue. In murine models, pregnancy followed by lactation and involution drove the accumulation of CD8⁺ T cells in the mammary gland, coinciding with reduced tumour growth and increased intratumoural immune cell infiltration, effects that were abrogated by CD8⁺ T cell depletion. Importantly, this CD8+ T cell dependent tumour control was only observed following a complete cycle of lactation and involution. Consistent with this, primary TNBCs from parous women exhibited greater T cell infiltration and improved clinical outcomes. Together these findings, spanning preclinical models and over 1000 patient samples, provide new insight into how reproductive history shapes breast immunity, positioning CD8⁺ T cells as key mediators of parity-associated protection and informing novel strategies for both prevention and treatment of breast cancer.