Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity

Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) and IFNγ reporter mice ( Nr4a3 -Tocky- Ifnγ -YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic tumour infiltrating lymphocytes (TILs) exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced central memory (T CM ) formation. Modelling of T-cell–tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector. Synopsis Attenuated Salmonella show promise as cancer therapeutics, yet T cells play no role in efficacy, limiting combined checkpoint blockade therapies or induction of immune memory. Improving T cell responses requires a better understanding of the causes of T cell dysfunction during Salmonella BCT. Attenuated Salmonella enterica Typhimurium (STm) cancer therapy drives T cell dysfunction. STm depletes asparagine via an asparaginase (ansB) in the tumour microenvironment (TME), suppressing tumour growth. Asparagine depletion in the TME triggers T cell metabolic arrest by destabilising c-Myc. An STm ∆ansB mutant restores T cell function but at the cost of enhanced tumour metabolism. The STm ∆ansB mutant still effectively reduces tumour growth in a mouse model. Attenuated Salmonella show promise as cancer therapeutics, yet T cells play no role in efficacy, limiting combined checkpoint blockade therapies or induction of immune memory. Improving T cell responses requires a better understanding of the causes of T cell dysfunction during Salmonella BCT.