PARP7 is a relevant target in cancer cells and is involved in several cellular processes, including type I interferon (IFN-I), aryl hydrocarbon receptor, estrogen receptor, and androgen receptor signaling, and stabilization of the oncogenic RAS-MAPK effector FRA1. Atamparib is the first PARP7 inhibitor in the clinic, with high potency and selectivity. It is orally bioavailable, with favorable safety profile in PhI/II trials both as single agent and in combination with anti-PD1 antibodies. Recent better understanding of PARP7 biology shed light on a unique atamparib dual mechanism of action, that combines direct cancer cell killing with innate immune activation via restoration of IFN-I signaling to assist adaptive response. This insight, along with new preclinical and clinical data, points to new indications and opportunity for combination. Atamparib biochemical and cellular characterization was conducted by HTRF, SPR and Nanobret. PARP7 crystal structure was determined by X-ray crystallography. In investigating atamparib antiproliferative activity, cancer cell lines from multiple indications have been treated with 0-10 μM of atamparib single agent for 144 hours. Combination with various standards of cares approved in each setting have been evaluated in 7x7 or 7x11 matrix. Atamparib subnamolar potency and long residence time on PARP7, selectivity versus other members of PARP family, and PARP7 target engagement in cell, were corroborated using biochemical and biophysical assays. The unprecedented crystal structure of PARP7 bound to atamparib was solved by X-ray crystallography at 2 Å resolution, confirming the proposed binding mode. Atamparib was proven to be efficacious in multiple high-unmet-need indications, demonstrating a remarkable anti-tumor activity in NSCLC adenocarcinoma at clinically achievable concentrations, particularly when oncogenic pathways are activated, due to KRAS or other oncogene drivers' mutations. These findings were validated through both in vitro and in vivo studies. Interestingly, atamparib sensitivity in NSCLC adenocarcinoma KRAS mutant is observed irrespective of the specific KRAS mutation involved. These data support the mechanistic link that connect PARP7 to RAS-MAPK pathway through FRA1, a potent oncogene frequently overexpressed in tumors, where it promotes proliferation, survival, and immune evasion. By inhibiting PARP7, atamparib induces FRA1 degradation, reactivates IFN-I signaling, and triggers tumor cell death and immune-mediated tumor clearance. Moreover, atamparib increases the activity of several standards of care and targeted drugs in late development in NSCLC when combined with them. Overall, our data shed light on a PARP7 dependency in NSCLC adenocarcinoma context and support atamparib development in this setting, both in monotherapy and in combination with multiple standards of care.